Substituted tetrahydrofurans as modulators of sodium channels

ABSTRACT

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Pat. Application No.17/112,156, filed Dec. 4, 2020, which claims the benefit of U.S.Provisional Application No. 62/944,869, filed Dec. 6, 2019, each ofwhich are incorporated by reference in their entirety.

BACKGROUND

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Neuropathic pain is a form of chronic pain caused by an injury to thesensory nerves (Dieleman, J.P., et al., Incidence rates and treatment ofneuropathic pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathic pain can be divided into two categories,pain caused by generalized metabolic damage to the nerve and pain causedby a discrete nerve injury. The metabolic neuropathies includepost-herpetic neuropathy, diabetic neuropathy, and drug-inducedneuropathy. Discrete nerve injury indications include post-amputationpain, post-surgical nerve injury pain, and nerve entrapment injurieslike neuropathic back pain.

Voltage-gated sodium channels (Na_(v)s) are involved in pain signaling.Na_(v)s are biological mediators of electrical signaling as they mediatethe rapid upstroke of the action potential of many excitable cell types(e.g. neurons, skeletal myocytes, cardiac myocytes). The evidence forthe role of these channels in normal physiology, the pathological statesarising from mutations in sodium channel genes, preclinical work inanimal models, and the clinical pharmacology of known sodium channelmodulating agents all point to the central role of Na_(v)s in painsensation (Rush, A.M. and T.R. Cummins, Painful Research: Identificationof a Small-Molecule Inhibitor that Selectively Targets Na_(v)1.8 SodiumChannels. Mol. Interv., 2007. 7(4): p. 192-5); England, S.,Voltage-gated sodium channels: the search for subtypeselectiveanalgesics. Expert Opin. Investig. Drugs 17 (12), p. 1849-64 (2008);Krafte, D. S. and Bannon, A. W., Sodium channels and nociception: recentconcepts and therapeutic opportunities. Curr. Opin. Pharmacol. 8 (1), p.50-56 (2008)). Na_(v)s mediate the rapid upstroke of the actionpotential of many excitable cell types (e.g. neurons, skeletal myocytes,cardiac myocytes), and thus are involved in the initiation of signalingin those cells (Hille, Bertil, Ion Channels of Excitable Membranes,Third ed. (Sinauer Associates, Inc., Sunderland, MA, 2001)). Because ofthe role Na_(v)s play in the initiation and propagation of neuronalsignals, antagonists that reduce Na_(v) currents can prevent or reduceneural signaling and Na_(v) channels have been considered likely targetsto reduce pain in conditions where hyper-excitability is observed(Chahine, M., Chatelier, A., Babich, O., and Krupp, J. J., Voltage-gatedsodium channels in neurological disorders. CNS Neurol. Disord. DrugTargets 7 (2), p. 144-58 (2008)). Several clinically useful analgesicshave been identified as inhibitors of Na_(v) channels. The localanesthetic drugs such as lidocaine block pain by inhibiting Na_(v)channels, and other compounds, such as carbamazepine, lamotrigine, andtricyclic antidepressants that have proven effective at reducing painhave also been suggested to act by sodium channel inhibition (Soderpalm,B., Anticonvulsants: aspects of their mechanisms of action. Eur. J. Pain6 Suppl. A, p. 3-9 (2002); Wang, G. K., Mitchell, J., and Wang, S. Y.,Block of persistent late Na⁺ currents by antidepressant sertraline andparoxetine. J. Membr. Biol. 222 (2), p. 79-90 (2008)).

The Na_(v)s form a subfamily of the voltage-gated ion channelsuper-family and comprises 9 isoforms, designated Na_(v)1.1 - Na_(v)1.9.The tissue localizations of the nine isoforms vary. Na_(v)1.4 is theprimary sodium channel of skeletal muscle, and Na_(v)1.5 is primarysodium channel of cardiac myocytes. Na_(v)s 1.7, 1.8 and 1.9 areprimarily localized to the peripheral nervous system, while Na_(v)s 1.1,1.2, 1.3, and 1.6 are neuronal channels found in both the central andperipheral nervous systems. The functional behaviors of the nineisoforms are similar but distinct in the specifics of theirvoltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L.,and Waxman, S. G., International Union of Pharmacology. XLVII.Nomenclature and structure-function relationships of voltage-gatedsodium channels. Pharmacol. Rev. 57 (4), p. 397 (2005)).

Upon their discovery, Na_(v)1.8 channels were identified as likelytargets for analgesia (Akopian, A.N., L. Sivilotti, and J.N. Wood, Atetrodotoxin-resistant voltage-gated sodium channel expressed by sensoryneurons. Nature, 1996. 379(6562): p. 257-62). Since then, Na_(v)1.8 hasbeen shown to be a carrier of the sodium current that maintains actionpotential firing in small dorsal root ganglia (DRG) neurons (Blair, N.T.and B.P. Bean, Roles of tetrodotoxin (TTX)-sensitive Na+ current,TTX-resistant Na⁺ current, and Ca²⁺ current in the action potentials ofnociceptive sensory neurons. J. Neurosci., 2002. 22(23): p. 10277-90).Na_(v)1.8 is involved in spontaneous firing in damaged neurons, likethose that drive neuropathic pain (Roza, C., et al., Thetetrodotoxin-resistant Na⁺ channel Na_(v)1.8 is essential for theexpression of spontaneous activity in damaged sensory axons of mice. J.Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M.F., et al., A-803467, apotent and selective Na_(v)1.8 sodium channel blocker, attenuatesneuropathic and inflammatory pain in the rat. Proc. Natl. Acad. Sci. U SA, 2007. 104(20): p. 8520-5; Joshi, S.K., et al., Involvement of theTTX-resistant sodium channel Na_(v)1.8 in inflammatory and neuropathic,but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82;Lai, J., et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, Na_(v)1.8. Pain, 2002.95(1-2): p. 143-52; Dong, X.W., et al., Small interfering RNA-mediatedselective knockdown of Na_(v)1.8 tetrodotoxin-resistant sodium channelreverses mechanical allodynia in neuropathic rats. Neuroscience, 2007.146(2): p. 812-21; Huang, H.L., et al., Proteomic profiling of neuromasreveals alterations in protein composition and local protein synthesisin hyper-excitable nerves. Mol. Pain, 2008. 4: p. 33; Black, J.A., etal., Multiple sodium channel isoforms and mitogen-activated proteinkinases are present in painful human neuromas. Ann. Neurol., 2008.64(6): p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 andNaN/SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p.41-50; Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-likeimmunoreactivity in human adult and neonate injured sensory nerves. FEBSLett., 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship ofaxonal voltage-gated sodium channel 1.8 (Na_(v)1.8) mRNA accumulation tosciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem.286(46): p. 39836-47). The small DRG neurons where Na_(v)1.8 isexpressed include the nociceptors involved in pain signaling. Na_(v)1.8mediates large amplitude action potentials in small neurons of thedorsal root ganglia (Blair, N.T. and B.P. Bean, Roles of tetrodotoxin(TTX)-sensitive Na⁺ current, TTX-resistant Na⁺ current, and Ca²⁺ currentin the action potentials of nociceptive sensory neurons. J. Neurosci.,2002. 22(23): p. 10277-90). Na_(v)1.8 is necessary for rapid repetitiveaction potentials in nociceptors, and for spontaneous activity ofdamaged neurons. (Choi, J.S. and S.G. Waxman, Physiological interactionsbetween Na_(v)1.7 and Na_(v)1.8 sodium channels: a computer simulationstudy. J. Neurophysiol. 106(6): p. 3173-84; Renganathan, M., T.R.Cummins, and S.G. Waxman, Contribution of Na(_(v)) 1.8 sodium channelsto action potential electrogenesis in DRG neurons. J. Neurophysiol.,2001. 86(2): p. 629-40; Roza, C., et al., The tetrodotoxin-resistant Na⁺channel Na_(v)1.8 is essential for the expression of spontaneousactivity in damaged sensory axons of mice. J. Physiol., 2003. 550(Pt 3):p. 921-6). In depolarized or damaged DRG neurons, Na_(v)1.8 appears tobe a driver of hyper-excitablility (Rush, A.M., et al., A single sodiumchannel mutation produces hyper- or hypoexcitability in different typesof neurons. Proc. Natl. Acad. Sci. USA, 2006. 103(21): p. 8245-50). Insome animal pain models, Na_(v)1.8 mRNA expression levels have beenshown to increase in the DRG (Sun, W., et al., Reduced conductionfailure of the main axon of polymodal nociceptive C-fibers contributesto painful diabetic neuropathy in rats. Brain, 135(Pt 2): p. 359-75;Strickland, I.T., et al., Changes in the expression of Na_(v)1.7,Na_(v)1.8 and Na_(v)1.9 in a distinct population of dorsal root gangliainnervating the rat knee joint in a model of chronic inflammatory jointpain. Eur. J. Pain, 2008. 12(5): p. 564-72; Qiu, F., et al., Increasedexpression of tetrodotoxin-resistant sodium channels Na_(v)1.8 andNa_(v)1.9 within dorsal root ganglia in a rat model of bone cancer pain.Neurosci. Lett., 512(2): p. 61-6).

The primary drawback to some known Na_(v) inhibitors is their poortherapeutic window, and this is likely a consequence of their lack ofisoform selectivity. Since Na_(v)1.8 is primarily restricted to theneurons that sense pain, selective Na_(v)1.8 blockers are unlikely toinduce the adverse events common to non-selective Na_(v) blockers.Accordingly, there remains a need to develop additional Na_(v) channelmodulators, preferably those that are highly potent and selective forNa_(v)1.8.

SUMMARY

In one aspect, the invention relates to a compound described herein, ora pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a pharmaceutical compositioncomprising the compound, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable carriers or vehicles.

In still another aspect, the invention relates to a method of inhibitinga voltage gated sodium channel in a subject by administering thecompound, pharmaceutically acceptable salt, or pharmaceuticalcomposition to the subject.

In yet another aspect, the invention relates to a method of treating orlessening the severity in a subject of a variety of diseases, disorders,or conditions, including, but not limited to, chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomypain, herniorrhaphy pain or abdominoplasty pain), visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, and cardiac arrhythmia, by administering thecompound, pharmaceutically acceptable salt, or pharmaceuticalcomposition to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an XRPD pattern characteristic of Compound 7, Form A.

FIG. 2 depicts TGA thermogram characteristic of Compound 7, Form A.

FIG. 3 depicts DSC thermogram characteristic of Compound 7, Form A.

FIG. 4 depicts an XRPD pattern characteristic of Compound 7, Form B.

FIG. 5 depicts a solid state ¹³C NMR spectrum characteristic of Compound7, Form B.

FIG. 6 depicts a solid state ¹⁹F NMR spectrum characteristic of Compound7, Form B.

FIG. 7 depicts a TGA thermogram characteristic of Compound 7, Form B.

FIG. 8 depicts a DSC thermogram characteristic of Compound 7, Form B.

FIG. 9 depicts an IR spectrum characteristic of Compound 7, Form B.

FIG. 10 depicts a thermal ellipsoid plot characteristic of Compound 7,Form B.

FIG. 11 depicts a thermal ellipsoid plot characteristic of Compound 9,Form A.

FIG. 12 depicts an XRPD pattern characteristic of Compound 11, Form A.

FIG. 13 depicts an XRPD pattern characteristic of Compound 11, Form B.

FIG. 14 depicts a thermal ellipsoid plot characteristic of Compound 11,Form A.

FIG. 15 depicts an XRPD pattern characteristic of Compound 19, Form A.

FIG. 16 depicts a solid state ¹³C NMR spectrum characteristic ofCompound 19, Form A.

FIG. 17 depicts a solid state ¹⁹F NMR spectrum characteristic ofCompound 19, Form A.

FIG. 18 depicts a thermal ellipsoid plot characteristic of Compound 19,Form A.

FIG. 19 depicts an XRPD pattern characteristic of Compound 22, Form A.

FIG. 20 depicts a solid state ¹³C NMR spectrum characteristic ofCompound 22, Form A.

FIG. 21 depicts a solid state ¹⁹F NMR spectrum characteristic ofCompound 22, Form A.

FIG. 22 depicts an XRPD pattern characteristic of Compound 23, Form A.

FIG. 23 depicts a solid state ¹³C NMR spectrum characteristic ofCompound 23, Form A.

FIG. 24 depicts a solid state ¹⁹F NMR spectrum characteristic ofCompound 23, Form A.

FIG. 25 depicts a thermal ellipsoid plot characteristic of Compound 23,Form A.

FIG. 26 depicts an XRPD pattern characteristic of Compound 25, Form A.

DETAILED DESCRIPTION

In one aspect, the invention relates to a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

-   X^(2a) is N, N⁺-O⁻, or C-R^(2a);-   X^(4a) is N, N⁺-O⁻, or C-R^(4a);-   X^(5a) is N, N⁺-O⁻, or C-R^(5a);-   X^(6a) is N, N⁺-O⁻, or C-R^(6a);-   each R is independently H or C₁-C₆ alkyl;-   R^(2a), R^(4a), R^(5a), and R^(6a) are each independently H, halo,    C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl, C₃-C₆    cycloalkyl, or C₁-C₆ haloalkyl;-   R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, C₃-C₆    cycloalkyl, or C₁-C₆ haloalkyl;-   X^(3c) is N or C-R^(3c);-   X^(4c) is N or C-R^(4c);-   X^(5c) is N or C-R^(5c);-   X^(6c) is N or C-R^(6c);-   R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl,    C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl),    wherein said cycloalkyl is optionally substituted with 1-2 halo;-   L¹ is a bond or O;-   L² is a bond or C₁-C₆ alkylene;-   R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(5c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and-   R^(6c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   provided that no more than two of X^(2a), X^(4a), X^(5a), and X^(6a)    are N or N⁺-O⁻; and-   provided that no more than one of X^(3c), X^(4c), X^(5c), and X^(6c)    are N.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(2a) isC-R^(2a); X^(5a) is C-R^(5a); X^(6a) is C-R^(6a); R^(4b1) and R^(4b2)are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(5b1) andR^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;X^(3c) is C-R^(3c); X^(4c) is C-R^(4c); X^(5c) is C-R^(5c); X^(6c) isC-R^(6c); and R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry,”Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’sAdvanced Organic Chemistry,” 5^(th) Ed., Ed.: Smith, M.B. and March, J.,John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As used herein, the term “compounds of the invention” refers to thecompounds of formulas (I), (I-A), (I-A-1), (I-B), (I-B-1), (I-C), and(I-C-1), and all of the embodiments thereof, as described herein, and tothe compounds identified in Table A, Table B, and Table C.

As described herein, the compounds of the invention comprise multiplevariable groups (e.g., R, X^(4a), R^(5b), etc.). As one of ordinaryskill in the art will recognize, combinations of groups envisioned bythis invention are those combinations that result in the formation ofstable or chemically feasible compounds. The term “stable,” in thiscontext, refers to compounds that are not substantially altered whensubjected to conditions to allow for their production, detection, andpreferably their recovery, purification, and use for one or more of thepurposes disclosed herein. In some embodiments, a stable compound orchemically feasible compound is one that is not substantially alteredwhen kept at a temperature of 40° C. or less, in the absence of moistureor other chemically reactive conditions, for at least a week.

The chemical structures depicted herein are intended to be understood asthey would be understood by one of ordinary skill in the art. Forexample, with respect to formulas (I), (I-A), (I-B), and (I-C), one ofordinary skill in the art would understand that X^(5a) and X^(6a) areconnected by a double bond and that X^(4c) and X^(5c) are connected by asingle bond, even though the bonds between these groups may be obscuredby the atom labels in the chemical structures. Moreover, one of ordinaryskill would understand that a substituent depicted as “CF₃” or “F₃C” ina chemical structure refers to a trifluoromethyl substituent, regardlessof which depiction appears in the chemical structure.

As used herein, the term “halo” means F, Cl, Br or I.

As used herein, the term “alkyl” refers to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing no unsaturation, and having the specified number ofcarbon atoms, which is attached to the rest of the molecule by a singlebond. For example, a “C₁-C₆ alkyl” group is an alkyl group havingbetween one and six carbon atoms.

As used herein, the term “haloalkyl” refers to an alkyl group having thespecified number of carbon atoms, wherein one or more of the hydrogenatoms of the alkyl group are replaced by halo groups. For example, a“C₁-C₆ haloalkyl” group is an alkyl group having between one and sixcarbon atoms, wherein one or more of the hydrogen atoms of the alkylgroup are replaced by halo groups.

As used herein, the term “alkenyl” refers to a straight or branchedhydrocarbon chain radical group consisting solely of carbon and hydrogenatoms, containing one or more carbon-carbon double bonds, and having thespecified number of carbon atoms, which is attached to the rest of themolecule by a single bond. For example, a “C₂-C₆ alkenyl” group is analkenyl group having between two and six carbon atoms.

As used herein, the term “cycloalkyl” refers to a stable, non-aromatic,mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbonradical consisting solely of carbon and hydrogen atoms, having thespecified number of carbon ring atoms, and which is attached to the restof the molecule by a single bond. For example, a “C₃-C₈ cycloalkyl”group is a cycloalkyl group having between three and eight carbon atoms.

As used herein, the term “alkylene” refers to a divalent, straight orbranched hydrocarbon chain radical group consisting solely of carbon andhydrogen atoms, containing no unsaturation, and having the specifiednumber of carbon atoms, which is attached to the rest of the molecule bytwo single bonds. For example, a “C₁-C₆ alkylene” group is an alkylenegroup having between one and six carbon atoms.

As used herein, the term “optionally substituted” refers to a group thatis either unsubstituted or substituted with the subsequently identifiedsubstituents. For example, a group that is “optionally substituted with1-2 halo” is either unsubstituted, substituted with 1 halo group, orsubstituted with 2 halo groups.

Unless otherwise specified, the compounds of the invention, whetheridentified by chemical name or chemical structure, include allstereoisomers (e.g., enantiomers and diastereomers), double bond isomers(e.g., (Z) and (E)), conformational isomers, and tautomers of thecompounds identified by the chemical names and chemical structuresprovided herein. In addition, single stereoisomers, double bond isomers,conformational isomers, and tautomers as well as mixtures ofstereoisomers, double bond isomers, conformational isomers, andtautomers are within the scope of the invention.

As used herein, in any chemical structure or formula, a bold or hashedstraight bond (

or

, respectively) attached to a stereocenter of a compound, such as in

denotes the relative stereochemistry of the stereocenter, relative toother stereocenter(s) to which bold or hashed straight bonds areattached.

As used herein, in any chemical structure or formula, a bold or hashedwedge bond (

or

, respectively) attached to a stereocenter of a compound, such as in

denotes the absolute stereochemistry of the stereocenter, as well as therelative stereochemistry of the stereocenter, relative to otherstereocenter(s) to which bold or hashed wedge bonds are attached.

As used herein, the prefix “rac-,” when used in connection with a chiralcompound, refers to a racemic mixture of the compound. In a compoundbearing the “rac-” prefix, the (R)- and (S)- designators in the chemicalname reflect the relative stereochemistry of the compound.

As used herein, the prefix “rel-,” when used in connection with a chiralcompound, refers to a single enantiomer of unknown absoluteconfiguration. In a compound bearing the “rel-” prefix, the (R)-and (S)-designators in the chemical name reflect the relative stereochemistry ofthe compound, but do not necessarily reflect the absolutestereochemistry of the compound.

As used herein, the term “compound,” when referring to the compounds ofthe invention, refers to a collection of molecules having identicalchemical structures, except that there may be isotopic variation amongthe constituent atoms of the molecules. The term “compound” includessuch a collection of molecules without regard to the purity of a givensample containing the collection of molecules. Thus, the term “compound”includes such a collection of molecules in pure form, in a mixture(e.g., solution, suspension, colloid, or pharmaceutical composition, ordosage form) with one or more other substances, or in the form of ahydrate, solvate, or co-crystal.

In the specification and claims, unless otherwise specified, any atomnot specifically designated as a particular isotope in any compound ofthe invention is meant to represent any stable isotope of the specifiedelement. In the Examples, where an atom is not specifically designatedas a particular isotope in any compound of the invention, no effort wasmade to enrich that atom in a particular isotope, and therefore a personof ordinary skill in the art would understand that such atom likely waspresent at approximately the natural abundance isotopic composition ofthe specified element.

As used herein, the term “stable,” when referring to an isotope, meansthat the isotope is not known to undergo spontaneous radioactive decay.Stable isotopes include, but are not limited to, the isotopes for whichno decay mode is identified in V.S. Shirley & C.M. Lederer, IsotopesProject, Nuclear Science Division, Lawrence Berkeley Laboratory, Tableof Nuclides (January 1980).

As used herein in the specification and claims, “H” refers to hydrogenand includes any stable isotope of hydrogen, namely ¹H and D. In theExamples, where an atom is designated as “H,” no effort was made toenrich that atom in a particular isotope of hydrogen, and therefore aperson of ordinary skill in the art would understand that such hydrogenatom likely was present at approximately the natural abundanceconcentration of hydrogen.

As used herein, “¹H” refers to protium. Where an atom in a compound ofthe invention, or a pharmaceutically acceptable salt thereof, isdesignated as protium, protium is present at the specified position atat least the natural abundance concentration of protium.

As used herein, “D,” “d,” and “²H” refer to deuterium.

In some embodiments, the compounds of the invention, andpharmaceutically acceptable salts thereof, include each constituent atomat approximately the natural abundance isotopic composition of thespecified element.

In some embodiments, the compounds of the invention, andpharmaceutically acceptable salts thereof, include one or more atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the most abundant isotope of the specified element(“isotope-labeled” compounds and salts). Examples of stable isotopeswhich are commercially available and suitable for the invention includewithout limitation isotopes of hydrogen, carbon, nitrogen, oxygen, andphosphorus, for example ²H, ¹³C, ¹⁵N, ¹³O, ¹⁷O, and ³¹P, respectively.

The isotope-labeled compounds and salts can be used in a number ofbeneficial ways, including as medicaments. In some embodiments, theisotope-labeled compounds and salts are deuterium (²H)-labeled.Deuterium (²H)-labeled compounds and salts are therapeutically usefulwith potential therapeutic advantages over the non-²H-labelledcompounds. In general, deuterium (²H)-labeled compounds and salts canhave higher metabolic stability as compared to those that are notisotope-labeled owing to the kinetic isotope effect described below.Higher metabolic stability translates directly into an increased in vivohalf-life or lower dosages, which under most circumstances wouldrepresent a preferred embodiment of the present invention. Theisotope-labeled compounds and salts can usually be prepared by carryingout the procedures disclosed in the synthesis schemes, the examples andthe related description, replacing a non-isotope-labeled reactant by areadily available isotope-labeled reactant.

The deuterium (²H)-labeled compounds and salts can manipulate the rateof oxidative metabolism of the compound by way of the primary kineticisotope effect. The primary kinetic isotope effect is a change of therate for a chemical reaction that results from exchange of isotopicnuclei, which in turn is caused by the change in ground state energiesof the covalent bonds involved in the reaction. Exchange of a heavierisotope usually results in a lowering of the ground state energy for achemical bond and thus causes a reduction in the rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexample, if deuterium is bonded to a carbon atom at a non-exchangeableposition, rate differences of k_(H/)k_(D)= 2-7 are typical. For afurther discussion, see S. L. Harbeson and R. D. Tung, Deuterium In DrugDiscovery and Development, Ann. Rep. Med. Chem. 2011, 46, 403-417,incorporated in its entirety herein by reference.

The concentration of an isotope (e.g., deuterium) incorporated at agiven position of an isotope-labeled compound of the invention, or apharmaceutically acceptable salt thereof, may be defined by the isotopicenrichment factor. The term “isotopic enrichment factor,” as usedherein, means the ratio between the abundance of an isotope at a givenposition in an isotope-labeled compound (or salt) and the naturalabundance of the isotope.

Where an atom in a compound of the invention, or a pharmaceuticallyacceptable salt thereof, is designated as deuterium, such compound (orsalt) has an isotopic enrichment factor for such atom of at least 3000(~45% deuterium incorporation). In some embodiments, the isotopicenrichment factor is at least 3500 (~52.5% deuterium incorporation), atleast 4000 (~60% deuterium incorporation), at least 4500 (~67.5%deuterium incorporation), at least 5000 (~75% deuterium incorporation),at least 5500 (~82.5% deuterium incorporation), at least 6000 (~90%deuterium incorporation), at least 6333.3 (~95% deuteriumincorporation), at least 6466.7 (~97% deuterium incorporation), at least6600 (~99% deuterium incorporation), or at last 6633.3 (~99.5% deuteriumincorporation).

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein each R is H. Inother embodiments, each R is independently H or CH₃. In otherembodiments, N(R)₂ is NHCH₃.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(2a) is N. Inother embodiments, X^(2a) is C-R^(2a). In some embodiments, R^(2a) is H,D, halo, or C₁-C₆ alkyl. In other embodiments, R^(2a) is H, D, F, orCH₃. In some embodiments, X^(2a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(2a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(2a) isC-R^(2a); and R^(2a) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N. Inother embodiments, X^(4a) is N⁺-O⁻. In other embodiments, X^(4a) isC-R^(4a). In some embodiments, R^(4a) is halo. In other embodiments,R^(4a) is H or halo. In other embodiments, R^(4a) is H or F. In otherembodiments, X^(4a) is C-F. In some embodiments, X^(4a) is N, N⁺-O⁻,C-H, or C-halo. In other embodiments, X^(4a) is N, N⁺-O⁻, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) isC-R^(4a); and R^(4a) is halo.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(5a) is N. Inother embodiments, X^(5a) is C-R^(5a). In some embodiments, R^(5a) is H,D, halo, or C₁-C₆ alkyl. In other embodiments, R^(5a) is H, D, F, orCH₃. In some embodiments, X^(5a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(5a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(5a) isC-R^(5a); and R^(5a) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(6a) is N. Inother embodiments, X^(6a) is C-R^(6a). In some embodiments, R^(6a) is H,D, halo, or C₁-C₆ alkyl. In other embodiments, R^(6a) is H, D, F, orCH₃. In some embodiments, X^(6a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(6a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(6a) isC-R^(6a); and R^(6a) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R^(4b1) andR^(4b2) are each independently H or C₁-C₆ alkyl. In other embodiments,R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl, or C₃-C₆cycloalkyl. In other embodiments, R^(4b1) and R^(4b2) are eachindependently H or CH₃. In other embodiments, R^(4b1) and R^(4b2) areeach independently H, CH₃, CH₂CH₃, or cyclopropyl. In other embodiments,R^(4b1) is C₁-C₆ alkyl, and R^(4b2) is H. In other embodiments, R^(4b1)is H, and R^(4b2) is C₁-C₆ alkyl. In other embodiments, R^(4b1) is CH₃,and R^(4b2) is H. In other embodiments, R^(4b1) is H, and R^(4b2) isCH₃.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R^(5b1) andR^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆ haloalkyl. In otherembodiments, R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl,or C₁-C₆ haloalkyl. In other embodiments, R^(5b1) and R^(5b2) are eachindependently H, CH₃, or CF₃. In other embodiments, R^(5b1) and R^(5b2)are each independently H, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CHF₂, CF₂CH₃,CH₂CF₃, or CF₃. In other embodiments, R^(5b1) is C₁-C₆ alkyl, andR^(5b2) is C₁-C₆ haloalkyl. In other embodiments, R^(5b1) is C₁-C₆haloalkyl, and R^(5b2) is C₁-C₆ alkyl. In other embodiments, R^(5b1) isCH₃, and R^(5b2) is CF₃. In other embodiments, R^(5b1) is CF₃, andR^(5b2) is CH₃.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R^(2c) is OH,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R^(2c) is OH,halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkyl isoptionally substituted with 1-2 halo. In other embodiments, R^(2c) is H.In other embodiments, R^(2c) is C₁-C₆ alkoxy. In other embodiments,R^(2c) is C₁-C₆ haloalkoxy. In other embodiments, R^(2c) is-L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkyl is optionallysubstituted with 1-2 halo. In other embodiments, R^(2c) is OH, OCH₃,OCD₃, OCH₂CH₃, or OCHF₂. In other embodiments, R^(2c) is H, F, CH₃,CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

In other embodiments, R^(2c) is OH. In other embodiments, R^(2c) isOCH₃. In other embodiments, R^(2c) is OCD₃. In other embodiments, R^(2c)is OCH₂CH₃. In other embodiments, R^(2c) is OCHF₂.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(3c) is N. Inother embodiments, X^(3c) is C-R^(3c). In other embodiments, R^(3c) isH, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In other embodiments, R^(3c)is H, CH₃, CH₂CH₃, CHF₂, CF₃, F, or Cl. In some embodiments, X^(3c) isN, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, or C-Cl.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(3c) isC-R^(3c); and R^(3c) is H, halo, or C₁-C₆ alkyl. In other embodiments,R^(3c) is halo. In other embodiments, R^(3c) is C₁-C₆ alkyl. In otherembodiments, R^(3c) is H, F, C1, or CH₃. In other embodiments, R^(3c) isH. In other embodiments, R^(3c) is F. In other embodiments, R^(3c) isCl. In other embodiments, R^(3c) is CH₃.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4c) is N. Inother embodiments, X^(4c) is C-R^(4c). In other embodiments, R^(4c) isH, halo, or C₁-C₆ haloalkyl. In other embodiments, R^(4c) is H, CHF₂,CF₃, or F. In some embodiments, X^(4c) is N, C-H, C-CHF₂, C-CF₃, or C-F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4c) isC-R^(4c); and R^(4c) is halo. In other embodiments, R^(4c) is F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(5c) is N. Inother embodiments, X^(5c) is C-R^(5c). In other embodiments, R^(5c) is Hor halo. In other embodiments, R^(5c) is H, D, or Cl. In someembodiments, X^(5c) is N, C-H, C-D, or C-Cl.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(5c) isC-R^(5c); and R^(5c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(6c) is N. Inother embodiments, X^(6c) is C-R^(6c). In other embodiments, R^(6c) is Hor halo. In other embodiments, R^(6c) is H or F. In some embodiments,X^(6c) is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(2a) is N, C-H,C-D, C-(C₁-C₆ alkyl), or C-halo; X^(4a) is N, N⁺-O⁻, C-H, or C-halo;X^(5a) is N, C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; X^(6a) is N, C-H,C-D, C-(C₁-C₆ alkyl), or C-halo; each R is H or CH₃; R^(4b1) and R^(4b2)are each independently H, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl; R^(5b1) andR^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;R^(2c) is OH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, or-L¹-L²-(C₃-C₆ cycloalkyl), wherein saidcycloalkyl is optionally substituted with 1-2 halo; X^(3c) is C-R^(3c);R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X^(4c) is C-R^(4c);R^(4c) is H, halo, or C₁-C₆ haloalkyl; X^(5c) is C-R^(5c); R^(5c) is Hor halo; X^(6c) is C-R^(6c); and R^(6c) is H or halo.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) and R^(4b2) are eachindependently H or C₁-C₆ alkyl; R^(5b1) and R^(5b2) are eachindependently C₁-C₆ alkyl or C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, orC₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c);R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(2a) is N, C-H,C-D, C-CH₃, or C-F; X^(4a) is N, N⁺-O⁻, C-H, or C-F; X^(5a) is N, C-H,C-D, C-CH₃, or C-F; X^(6a) is N, C-H, C-D, C-CH₃, or C-F; each R is H orCH₃; R^(4b1) and R^(4b2) are each independently H, CH₃, CH₂CH₃, orcyclopropyl; R^(5b1) and R^(5b2) are each independently H, CH₃, CH₂CH₃,CH(CH₃)₂, C(CH₃)₃, CHF₂, CF₂CH₃, CH₂CF₃, or CF₃; R^(2c) is H, F, CH₃,CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

X^(3c) is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, or C-Cl; X^(4c)is N, C-H, C-CHF₂, C-CF₃, or C-F; X^(5c) is N, C-H, C-D, or C-Cl; andX^(6c) is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) and R^(4b2) are eachindependently H or CH₃; R^(5b1) and R^(5b2) are each independently H,CH₃, or CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) isC-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c)is halo; X^(5c) is C-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c)is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is C₁-C₆ alkyl; R^(4b2) isH; R^(5b1) is C₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c) is OH,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H,halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is H; R^(4b2) is C₁-C₆alkyl; R^(5b1) is C₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c) is OH,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H,halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is C₁-C₆ alkyl; R^(4b2) isH; R^(5b1) is C₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c) is OH,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H,halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is C₁-C₆ haloalkyl; R^(5b2)is C₁-C₆ alkyl; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl; R^(2c) is C₁-C₆alkoxy or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, orC₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c);R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CH₃; R^(5b2) is CF₃;R^(4b1) is CH₃; R^(4b2) is H; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CH₃; R^(5b2) is CF₃;R^(4b1) is H; R^(4b2) is CH₃; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CF₃; R^(5b2) is CH₃;R^(4b1) is CH₃; R^(4b2) is H; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein X^(4a) is N; eachR is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a); R^(5a) isH; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CF₃; R^(5b2) is CH₃;R^(4b1) is H, and R^(4b2) is CH₃; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula (I)(including any of the foregoing embodiments thereof), i.e., the compoundin non-salt form.

In some embodiments, the invention relates to a compound of formula(I-A)

or a pharmaceutically acceptable salt thereof, wherein:

-   X^(2a) is N, N⁺-O⁻, or C-R^(2a);-   X^(4a) is N, N⁺-O⁻, or C-R^(4a);-   X^(5a) is N, N⁺-O⁻, or C-R^(5a);-   X^(6a) is N, N⁺-O⁻, or C-R^(6a);-   each R is independently H or C₁-C₆ alkyl;-   R^(2a), R^(4a), R^(5a), and R^(6a) are each independently H, halo,    C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl, C₃-C₆    cycloalkyl, or C₁-C₆ haloalkyl;-   R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, C₃-C₆    cycloalkyl, or C₁-C₆ haloalkyl;-   X^(3c) is N or C-R^(3c);-   X^(4c) is N or C-R^(4c);-   X^(5c) is N or C-R^(5c);-   X^(6c) is N or C-R^(6c);-   R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl,    C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl),    wherein said cycloalkyl is optionally substituted with 1-2 halo;-   L¹ is a bond or O;-   L² is a bond or C₁-C₆ alkylene;-   R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(5c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and-   R^(6c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   provided that no more than two of X^(2a), X^(4a), X^(5a), and X^(6a)    are N or N⁺-O⁻; and-   provided that no more than one of X^(3c), X^(4c), X^(5c), and X^(6c)    are N.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isC-R^(2a); X^(5a) is C-R^(5a); X^(6a) is C-R^(6a); R^(4b1) and R^(4b2)are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(5b1) andR^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;X^(3c) is C-R^(3c); X^(4c) is C-R^(4c); X^(5c) is C-R^(5c); X^(6c) isC-R^(6c); and R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein each R isH. In other embodiments, each R is independently H or CH₃. In otherembodiments, N(R)₂ is NHCH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN. In other embodiments, X^(2a) is C-R^(2a). In some embodiments, R^(2a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(2a) is H, D, F,or CH₃. In some embodiments, X^(2a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(2a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isC-R^(2a); and R^(2a) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN. In other embodiments, X^(4a) is N⁺-O⁻. In other embodiments, X^(4a)is C-R^(4a). In some embodiments, R^(4a) is halo. In other embodiments,R^(4a) is H or halo. In other embodiments, R^(4a) is H or F. In otherembodiments, X^(4a) is C-F. In some embodiments, X^(4a) is N, N⁺-O⁻,C-H, or C-halo. In other embodiments, X^(4a) is N, N⁺-O⁻, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isC-R^(4a); and R^(4a) is halo.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(5a) isN. In other embodiments, X^(5a) is C-R^(5a). In some embodiments, R^(5a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(5a) is H, D, F,or CH₃. In some embodiments, X^(5a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(5a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(5a) isC-R^(5a); and R^(5a) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(6a) isN. In other embodiments, X^(6a) is C-R^(6a). In some embodiments, R^(6a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(6a) is H, D, F,or CH₃. In some embodiments, X^(6a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(6a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(6a) isC-R^(6a); and R^(6a) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R^(4b1)and R^(4b2) are each independently H or C₁-C₆ alkyl. In otherembodiments, R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl. In other embodiments, R^(4b1) and R^(4b2) are eachindependently H or CH₃. In other embodiments, R^(4b1) and R^(4b2) areeach independently H, CH₃, CH₂CH₃, or cyclopropyl. In other embodiments,R^(4b1) is C₁-C₆ alkyl, and R^(4b2) is H. In other embodiments, R^(4b1)is H, and R^(4b2) is C₁-C₆ alkyl. In other embodiments, R^(4b1) is CH₃,and R^(4b2) is H. In other embodiments, R^(4b1) is H, and R^(4b2) isCH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R^(5b1)and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆ haloalkyl. Inother embodiments, R^(5b1) and R^(5b2) are each independently H, C₁-C₆alkyl, or C₁-C₆ haloalkyl. In other embodiments, R^(5b1) and R^(5b2) areeach independently H, CH₃, or CF₃. In other embodiments, R^(5b1) andR^(5b2) are each independently H, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CHF₂,CF₂CH₃, CH₂CF₃, or CF₃. In other embodiments, R^(5b1) is C₁-C₆ alkyl,and R^(5b2) is C₁-C₆ haloalkyl. In other embodiments, R^(5b1) is C₁-C₆haloalkyl, and R^(5b2) is C₁-C₆ alkyl. In other embodiments, R^(5b1) isCH₃, and R^(5b2) is CF₃. In other embodiments, R^(5b1) is CF₃, andR^(5b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R^(2c) isOH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R^(2c) isOH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkylis optionally substituted with 1-2 halo. In other embodiments, R^(2c) isH. In other embodiments, R^(2c) is C₁-C₆ alkoxy. In other embodiments,R^(2c) is C₁-C₆ haloalkoxy. In other embodiments, R^(2c) is-L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkyl is optionallysubstituted with 1-2 halo. In other embodiments, R^(2c) is OH, OCH₃,OCD₃, OCH₂CH₃, or OCHF₂. In other embodiments, R^(2c) is H, F, CH₃,CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

In other embodiments, R^(2c) is OH. In other embodiments, R^(2c) isOCH₃. In other embodiments, R^(2c) is OCD₃. In other embodiments, R^(2c)is OCH₂CH₃. In other embodiments, R^(2c) is OCHF₂.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(3c) isN. In other embodiments, X^(3c) is C-R^(3c). In other embodiments,R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In otherembodiments, R^(3c) is H, CH₃, CH₂CH₃, CHF₂, CF₃, F, or Cl. In someembodiments, X^(3c) is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, orC-Cl.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(3c) isC-R^(3c); and R^(3c) is H, halo, or C₁-C₆ alkyl. In other embodiments,R^(3c) is halo. In other embodiments, R^(3c) is C₁-C₆ alkyl. In otherembodiments, R^(3c) is H, F, Cl, or CH₃. In other embodiments, R^(3c) isH. In other embodiments, R^(3c) is F. In other embodiments, R^(3c) isCl. In other embodiments, R^(3c) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4c) isN. In other embodiments, X^(4c) is C-R^(4c). In other embodiments,R^(4c) is H, halo, or C₁-C₆ haloalkyl. In other embodiments, R^(4c) isH, CHF₂, CF₃, or F. In some embodiments, X^(4c) is N, C-H, C-CHF₂,C-CF₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4c) isC-R^(4c); and R^(4c) is halo. In other embodiments, R^(4c) is F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(5c) isN. In other embodiments, X^(5c) is C-R^(5c). In other embodiments,R^(5c) is H or halo. In other embodiments, R^(5c) is H, D, or Cl. Insome embodiments, X^(5c) is N, C-H, C-D, or C-Cl.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(5c) isC-R^(5c); and R^(5c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(6c) isN. In other embodiments, X^(6c) is C-R^(6c). In other embodiments,R^(6c) is H or halo. In other embodiments, R^(6c) is H or F. In someembodiments, X^(6c) is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein R^(6c) isH.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN, C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; X^(4a) is N, N⁺-O⁻, C-H, orC-halo; X^(5a) is N, C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; X^(6a) is N,C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; each R is H or CH₃; R^(4b1) andR^(4b2) are each independently H, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆haloalkyl; R^(2c) is OH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl),wherein said cycloalkyl is optionally substituted with 1-2 halo; X^(3c)is C-R^(3c); R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X^(4c)is C-R^(4c); R^(4c) is H, halo, or C₁-C₆ haloalkyl; X^(5c) is C-R^(5c);R^(5c) is H or halo; X^(6c) is C-R^(6c); and R^(6c) is H or halo.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) and R^(4b2) areeach independently H or C₁-C₆ alkyl; R^(5b1) and R^(5b2) are eachindependently C₁-C₆ alkyl or C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, orC₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c);R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN, C-H, C-D, C-CH₃, or C-F; X^(4a) is N, N⁺-O⁻, C-H, or C-F; X^(5a) isN, C-H, C-D, C-CH₃, or C-F; X^(6a) is N, C-H, C-D, C-CH₃, or C-F; each Ris H or CH₃; R^(4b1) and R^(4b2) are each independently H, CH₃, CH₂CH₃,or cyclopropyl; R^(5b1) and R^(5b2) are each independently H, CH₃,CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CHF₂, CF₂CH₃, CH₂CF₃, or CF₃; R^(2c) is H, F,CH₃, CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

X^(3c) is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, or C-Cl; X^(4c)is N, C-H, C-CHF₂, C-CF₃, or C-F; X^(5c) is N, C-H, C-D, or C-Cl; andX^(6c) is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) and R^(4b2) areeach independently H or CH₃; R^(5b1) and R^(5b2) are each independentlyH, CH₃, or CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c)is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c);R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); andR^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is C₁-C₆ alkyl;R^(4b2) is H; R^(5b1) is C₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is H; R^(4b2) isC₁-C₆ alkyl; R^(5b1) is C₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is C₁-C₆ alkyl;R^(4b2) is H; R^(5b1) is C₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R4^(c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is C₁-C₆haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl;R^(2c) is C₁-C₆ alkoxy or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c)is H, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c)is C-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CH₃; R^(5b2) isCF₃; R^(4b1) is CH₃; R^(4b2) is H; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CH₃; R^(5b2) isCF₃; R^(4b1) is H; R^(4b2) is CH₃; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CF₃; R^(5b2) isCH₃; R^(4b1) is CH₃; R^(4b2) is H; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CF₃; R^(5b2) isCH₃; R^(4b1) is H, and R^(4b2) is CH₃; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-A) (including any of the foregoing embodiments thereof), i.e., thecompound in non-salt form.

In some embodiments, the invention relates to a compound of formula(I-A-1)

or a pharmaceutically acceptable salt thereof, wherein:

-   X^(4a) is N, N⁺-O⁻, or C-R^(4a);-   each R is independently H or C₁-C₆ alkyl;-   R^(4a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆    haloalkyl;-   R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆    haloalkyl;-   R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,    or C₁-C₆ haloalkoxy;-   R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and-   R^(4c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N. In other embodiments, X^(4a) is N⁺-O⁻. In other embodiments,X^(4a) is C-R^(4a). In other embodiments, X^(4a) is C-F.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein each Ris H. In other embodiments, each R is independently H or CH₃. In otherembodiments, N(R)₂ is NHCH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R^(4a)is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R^(4b1)and R^(4b2) are each independently H or C₁-C₆ alkyl. In otherembodiments, R^(4b1) and R^(4b2) are each independently H or CH₃. Inother embodiments, R^(4b1) is C₁-C₆ alkyl, and R^(4b2) is H. In otherembodiments, R^(4b1) is H, and R^(4b2) is C₁-C₆ alkyl. In otherembodiments, R^(4b1) is CH₃, and R^(4b2) is H. In other embodiments,R^(4b1) is H, and R^(4b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R^(5b1)and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆ haloalkyl. Inother embodiments, R^(5b1) and R^(5b2) are each independently H, CH₃, orCF₃. In other embodiments, R^(5b1) is C₁-C₆ alkyl, and R^(5b2) is C₁-C₆haloalkyl. In other embodiments, R^(5b1) is C₁-C₆ haloalkyl, and R^(5b2)is C₁-C₆ alkyl. In other embodiments, R^(5b1) is CH₃, and R^(5b2) isCF₃. In other embodiments, R^(5b1) is CF₃, and R^(5b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R^(2c)is C₁-C₆ alkoxy. In other embodiments, R^(2c) is C₁-C₆ haloalkoxy. Inother embodiments, R^(2c) is OH, OCH₃, OCD₃, OCH₂CH₃, or OCHF₂. In otherembodiments, R^(2c) is OH. In other embodiments, R^(2c) is OCH₃. Inother embodiments, R^(2c) is OCD₃. In other embodiments, R^(2c) isOCH₂CH₃. In other embodiments, R^(2c) is OCHF₂.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R^(3c)is H, halo, or C₁-C₆ alkyl. In other embodiments, R^(3c) is halo. Inother embodiments, R^(3c) is C₁-C₆ alkyl. In other embodiments, R^(3c)is H, F, Cl, or CH₃. In other embodiments, R^(3c) is H. In otherembodiments, R^(3c) is F. In other embodiments, R^(3c) is Cl. In otherembodiments, R^(3c) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein R^(4c)is halo. In other embodiments, R^(4c) is F.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) and R^(4b2) are each independently H or C₁-C₆alkyl; R^(5b1) and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) and R^(4b2) are each independently H or CH₃;R^(5b1) and R^(5b2) are each independently H, CH₃, or CF₃; R^(2c) is OH,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl;and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is C₁-C₆ alkyl; R^(4b2) is H; R^(5b1) isC₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl; R^(5b1) isC₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is C₁-C₆ alkyl; R^(4b2) is H; R^(5b1) isC₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl; R^(5b1) isC₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is CH₃; R^(4b2) is H; R^(5b1) is CH₃; R^(5b2)is CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is CH₃; R^(5b1) is CH₃; R^(5b2)is CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is CH₃; R^(4b2) is H; R^(5b1) is CF₃; R^(5b2)is CH₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H, and R^(4b2) is CH₃; R^(5b1) is CF₃;R^(5b2) is CH₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c)is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-A-1) (including any of the foregoing embodiments thereof), i.e., thecompound in non-salt form.

In some embodiments, the invention relates to a compound of formula(I-B)

or a pharmaceutically acceptable salt thereof, wherein:

-   X^(2a) is N, N⁺-O⁻, or C-R^(2a);-   X^(4a) is N, N⁺-O⁻, or C-R^(4a) _(;)-   X^(5a) is N, N⁺-O⁻, or C-R^(5a);-   X^(6a) is N, N⁺-O⁻, or C-R^(6a);-   each R is independently H or C₁-C₆ alkyl;-   R^(2a), R^(4a), R^(5a), and R^(6a) are each independently H, halo,    C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl, C₃-C₆    cycloalkyl, or C₁-C₆ haloalkyl;-   R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, C₃-C₆    cycloalkyl, or C₁-C₆ haloalkyl;-   X^(3c) is N or C-R^(3c);-   X^(4c) is N or C-R^(4c);-   X^(5c) is N or C-R^(5c);-   X^(6c) is N or C-R^(6c);-   R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl,    C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or -L¹-L²-(C₂-C₆ cycloalkyl),    wherein said cycloalkyl is optionally substituted with 1-2 halo;-   L¹ is a bond or O;-   L² is a bond or C₁-C₆ alkylene;-   R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(5c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and-   R^(6c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   provided that no more than two of X^(2a), X^(4a), X^(5a), and X^(6a)    are N or N⁺-O⁻; and-   provided that no more than one of X^(3c), X^(4c), X^(5c), and X^(6c)    are N.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein x^(2a) isC-R^(2a); X^(5a) is C-R^(5a); X^(6a) is C-R^(6a); R^(4b1) and R^(4b2)are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(5b1) andR^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;X^(3c) is C-R^(3c); X^(4c) is C-R^(4c); X^(5c) is C-R^(5c); X^(6c) isC-R^(6c); and R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein each R isH. In other embodiments, each R is independently H or CH₃. In otherembodiments, N(R)₂ is NHCH₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN. In other embodiments, X^(2a) is C-R^(2a). In some embodiments, R^(2a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(2a) is H, D, F,or CH₃. In some embodiments, x^(2a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(2a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isC-R^(2a); and R^(2a) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN. In other embodiments, X^(4a) is N⁺-O⁻. In other embodiments, x^(4a)is C-R^(4a). In some embodiments, R^(4a) is halo. In other embodiments,R^(4a) is H or halo. In other embodiments, R^(4a) is H or F. In otherembodiments, X^(4a) is C-F. In some embodiments, X^(4a) is N, N⁺-O⁻,C-H, or C-halo. In other embodiments, X^(4a) is N, N⁺-O⁻, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isC-R^(4a); and R^(4a) is halo.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(5a) isN. In other embodiments, X^(5a) is C-R^(5a). In some embodiments, R^(5a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(5a) is H, D, F,or CH₃. In some embodiments, X^(5a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(5a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(5a) isC-R^(5a); and R^(5a) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(6a) isN. In other embodiments, X^(6a) is C-R^(6a). In some embodiments, R^(6a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(6a) is H, D, F,or CH₃. In some embodiments, X^(6a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(6a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(6a) isC-R^(6a); and R^(6a) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R^(4b1)and R^(4b2) are each independently H or C₁-C₆ alkyl. In otherembodiments, R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl. In other embodiments, R^(4b1) and R^(4b2) are eachindependently H or CH₃. In other embodiments, R^(4b1) and R^(4b2) areeach independently H, CH₃, CH₂CH₃, or cyclopropyl. In other embodiments,R^(4b1) is C₁-C₆ alkyl, and R^(4b2) is H. In other embodiments, R^(4b1)is H, and R^(4b2) is C₁-C₆ alkyl. In other embodiments, R^(4b1) is CH₃,and R^(4b2) is H. In other embodiments, R^(4b1) is H, and R^(4b2) isCH₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R^(5b1)and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆ haloalkyl. Inother embodiments, R^(5b1) and R^(5b2) are each independently H, C₁-C₆alkyl, or C₁-C₆ haloalkyl. In other embodiments, R^(5b1) and R^(5b2) areeach independently H, CH₃, or CF₃. In other embodiments, R^(5b1) andR^(5b2) are each independently H, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CHF₂,CF₂CH₃, CH₂CF₃, or CF₃. In other embodiments, R^(5b1) is C₁-C₆ alkyl,and R^(5b2) is C₁-C₆ haloalkyl. In other embodiments, R^(5b1) is C₁-C₆haloalkyl, and R^(5b2) is C₁-C₆ alkyl. In other embodiments, R^(5b1) isCH₃, and R^(5b2) is CF₃. In other embodiments, R^(5b1) is CF₃, andR^(5b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R^(2c) isOH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R^(2c) isOH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkylis optionally substituted with 1-2 halo. In other embodiments, R^(2c) isH. In other embodiments, R^(2c) is C₁-C₆ alkoxy. In other embodiments,R^(2c) is C₁-C₆ haloalkoxy. In other embodiments, R^(2c) is-L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkyl is optionallysubstituted with 1-2 halo. In other embodiments, R^(2c) is OH, OCH₃,OCD₃, OCH₂CH₃, or OCHF₂. In other embodiments, R^(2c) is H, F, CH₃,CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

In other embodiments, R^(2c) is OH. In other embodiments, R^(2c) isOCH₃. In other embodiments, R^(2c) is OCD₃. In other embodiments, R^(2c)is OCH₂CH₃. In other embodiments, R^(2c) is OCHF₂.

In some embodiments, the invention relates to a compound of formula(I-B) or a pharmaceutically acceptable salt thereof, wherein X^(3c) isN. In other embodiments, X^(3c) is C-R^(3c). In other embodiments,R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In otherembodiments, R^(3c) is H, CH₃, CH₂CH₃, CHF₂, CF₃, F, or Cl. In someembodiments, X^(3c) is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, orC-Cl.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(3c) isC-R^(3c); and R^(3c) is H, halo, or C₁-C₆ alkyl. In other embodiments,R^(3c) is halo. In other embodiments, R^(3c) is C₁-C₆ alkyl. In otherembodiments, R^(3c) is H, F, Cl, or CH₃. In other embodiments, R^(3c) isH. In other embodiments, R^(3c) is F. In other embodiments, R^(3c) isCl. In other embodiments, R^(3c) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4c) isN. In other embodiments, X^(4c) is C-R^(4c). In other embodiments,R^(4c) is H, halo, or C₁-C₆ haloalkyl. In other embodiments, R^(4c) isH, CHF₂, CF₃, or F. In some embodiments, X^(4c) is N, C-H, C-CHF₂,C-CF₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4c) isC-R^(4c); and R^(4c) is halo. In other embodiments, R^(4c) is F.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(5c) isN. In other embodiments, X^(5c) is C-R^(5c). In other embodiments,R^(5c) is H or halo. In other embodiments, R^(5c) is H, D, or Cl. Insome embodiments, X^(5c) is N, C-H, C-D, or C-Cl.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(5c) isC-R^(5c); and R^(5c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(6c) isN. In other embodiments, X^(6c) is C-R^(6c). In other embodiments,R^(6c) is H or halo. In other embodiments, R^(6c) is H or F. In someembodiments, X^(6c) is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(IB), or a pharmaceutically acceptable salt thereof, wherein R^(6c) isH.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN, C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; X^(4a) is N, N⁺-O⁻, C-H, orC-halo; X^(5a) is N, C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; X^(6a) is N,C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; each R is H or CH₃; R^(4b1) andR^(4b2) are each independently H, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆haloalkyl; R^(2c) is OH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl),wherein said cycloalkyl is optionally substituted with 1-2 halo; X^(3c)is C-R^(3c); R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X^(4c)is C-R^(4c); R^(4c) is H, halo, or C₁-C₆ haloalkyl; X^(5c) is C-R^(5c);R^(5c) is H or halo; X^(6c) is C-R^(6c); and R^(6c) is H or halo.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) and R^(4b2) areeach independently H or C₁-C₆ alkyl; R^(5b1) and R^(5b2) are eachindependently C₁-C₆ alkyl or C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, orC₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c);R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN, C-H, C-D, C-CH₃, or C-F; X^(4a) is N, N⁺-O⁻, C-H, or C-F; X^(5a) isN, C-H, C-D, C-CH₃, or C-F; X^(6a) is N, C-H, C-D, C-CH₃, or C-F; each Ris H or CH₃; R^(4b1) and R^(4b2) are each independently H, CH₃, CH₂CH₃,or cyclopropyl; R^(5b1) and R^(5b2) are each independently H, CH₃,CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CHF₂, CF₂CH₃, CH₂CF₃, or CF₃; R^(2c) is H, F,CH₃, CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

X^(3c) is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, or C-Cl; X^(4c)is N, C-H, C-CHF₂, C-CF₃, or C-F; X^(5c) is N, C-H, C-D, or C-Cl; andX^(6c) is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) and R^(4b2) areeach independently H or CH₃; R^(5b1) and R^(5b2) are each independentlyH, CH₃, or CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c)is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c);R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); andR^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is C₁-C₆ alkyl;R^(4b2) is H; R^(5b1) is C₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is H; R^(4b2) isC₁-C₆ alkyl; R^(5b1) is C₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is C₁-C₆ alkyl;R^(4b2) is H; R^(5b1) is C₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is C₁-C₆haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl;R^(2c) is C₁-C₆ alkoxy or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c)is H, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c)is C-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CH₃; R^(5b2) isCF₃; R^(4b1) is CH₃; R^(4b2) is H; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CH₃; R^(5b2) isCF₃; R^(4b1) is H; R^(4b2) is CH₃; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; x^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CF₃; R^(5b2) isCH₃; R^(4b1) is CH₃; R^(4b2) is H; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CF₃; R^(5b2) isCH₃; R^(4b1) is H, and R^(4b2) is CH₃; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-B) (including any of the foregoing embodiments thereof), i.e., thecompound in non-salt form.

In some embodiments, the invention relates to a compound of formula(I-B-1)

or a pharmaceutically acceptable salt thereof, wherein:

-   X^(4a) is N, N⁺-O⁻, or C-R^(4a);-   each R is independently H or C₁-C₆ alkyl;-   R^(4a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆    haloalkyl;-   R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆    haloalkyl;-   R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,    or C₁-C₆ haloalkoxy;-   R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and-   R^(4c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N. In other embodiments, X^(4a) is N⁺-O⁻. In other embodiments,X^(4a) is C-R^(4a). In some embodiments, R^(4a) is halo. In otherembodiments, X^(4a) is C-F.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein each Ris H. In other embodiments, each R is independently H or CH₃. In otherembodiments, N(R)₂ is NHCH₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R^(4a)is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R^(4b1)and R^(4b2) are each independently H or C₁-C₆ alkyl. In otherembodiments, R^(4b1) and R^(4b2) are each independently H or CH₃. Inother embodiments, R^(4b1) is C₁-C₆ alkyl, and R^(4b2) is H. In otherembodiments, R^(4b1) is H, and R^(4b2) is C₁-C₆ alkyl. In otherembodiments, R^(4b1) is CH₃, and R^(4b2) is H. In other embodiments,R^(4b1) is H, and R^(4b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R^(5b1)and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆ haloalkyl. Inother embodiments, R^(5b1) and R^(5b2) are each independently H, CH₃, orCF₃. In other embodiments, R^(5b1) is C₁-C₆ alkyl, and R^(5b2) is C₁-C₆haloalkyl. In other embodiments, R^(5b1) is C₁-C₆ haloalkyl, and R^(5b2)is C₁-C₆ alkyl. In other embodiments, R^(5b1) is CH₃, and R^(5b2) isCF₃. In other embodiments, R^(5b1) is CF₃, and R^(5b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R^(2c)is C₁-C₆ alkoxy. In other embodiments, R^(2c) is C₁-C₆ haloalkoxy. Inother embodiments, R^(2c) is OH, OCH₃, OCD₃, OCH₂CH₃, or OCHF₂. In otherembodiments, R^(2c) is OH. In other embodiments, R^(2c) is OCH₃. Inother embodiments, R^(2c) is OCD₃. In other embodiments, R^(2c) isOCH₂CH₃. In other embodiments, R^(2c) is OCHF₂.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R^(3c)is H, halo, or C₁-C₆ alkyl. In other embodiments, R^(3c) is halo. Inother embodiments, R^(3c) is C₁-C₆ alkyl. In other embodiments, R^(3c)is H, F, Cl, or CH₃. In other embodiments, R^(3c) is H. In otherembodiments, R^(3c) is F. In other embodiments, R^(3c) is Cl. In otherembodiments, R^(3c) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein R^(4c)is halo. In other embodiments, R^(4c) is F.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) and R^(4b2) are each independently H or C₁-C₆alkyl; R^(5b1) and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) and R^(4b2) are each independently H or CH₃;R^(5b1) and R^(5b2) are each independently H, CH₃, or CF₃; R^(2c) is OH,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl;and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is C₁-C₆ alkyl; R^(4b2) is H; R^(5b1) isC₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl; R^(5b1) isC₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is C₁-C₆ alkyl; R^(4b2) is H; R^(5b1) isC₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl; R^(5b1) isC₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is CH₃; R^(4b2) is H; R^(5b1) is CH₃; R^(5b2)is CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is CH₃; R^(5b1) is CH₃; R^(5b2)is CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is CH₃; R^(4b2) is H; R^(5b1) is CF₃; R^(5b2)is CH₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H, and R^(4b2) is CH₃; R^(5b1) is CF₃;R^(5b2) is CH₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c)is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-B-1) (including any of the foregoing embodiments thereof), i.e., thecompound in non-salt form.

In some embodiments, the invention relates to a compound of formula(I-C)

or a pharmaceutically acceptable salt thereof, wherein:

-   X^(2a) is N, N⁺-O⁻, or C-R^(2a);-   x^(4a) is N, N⁺-O⁻, or C-R^(4a);-   X^(5a) is N, N⁺-O⁻, or C-R^(5a);-   X^(6a) is N, N⁺-O⁻, or C-R^(6a);-   each R is independently H or C₁-C₆ alkyl;-   R^(2a), R^(4a), R^(5a), and R^(6a) are each independently H, halo,    C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl, C₃-C₆    cycloalkyl, or C₁-C₆ haloalkyl;-   R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, C₃-C₆    cycloalkyl, or C₁-C₆ haloalkyl;-   X^(3c) is N or C-R^(3c);-   X^(4c) is N or C-R^(4c);-   X^(5c) is N or C-R^(5c)-   X^(6c) is N or C-R^(6c);-   R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl,    C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl),    wherein said cycloalkyl is optionally substituted with 1-2 halo;-   L¹ is a bond or O;-   L² is a bond or C₁-C₆ alkylene;-   R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(5c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and-   R^(6c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   provided that no more than two of X^(2a), X^(4a), X^(5a), and X^(6a)    are N or N⁺-O⁻; and-   provided that no more than one of X^(3c), X^(4c), X^(5c), and X^(6c)    are N.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isC-R^(2a); X^(5a) is C-R^(5a); X^(6a) is C-R^(6a); R^(4b1) and R^(4b2)are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(5b1) andR^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;X^(3c) is C-R^(3c); X^(4c) is C-R^(4c); X^(5c) is C-R^(5c); X^(6c) isC-R^(6c); and R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein each R isH. In other embodiments, each R is independently H or CH₃. In otherembodiments, N(R)₂ is NHCH₃.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN. In other embodiments, X^(2a) is C-R^(2a). In some embodiments, R^(2a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(2a) is H, D, F,or CH₃. In some embodiments, X^(2a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(2a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isC-R^(2a); and R^(2a) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN. In other embodiments, X^(4a) is N⁺-O⁻. In other embodiments, X^(4a)is C-R^(4a). In some embodiments, R^(4a) is halo. In other embodiments,R^(4a) is H or halo. In other embodiments, R^(4a) is H or F. In otherembodiments, X^(4a) is C-F. In some embodiments, X^(4a) is N, N⁺-O⁻,C-H, or C-halo. In other embodiments, X^(4a) is N, N⁺-O⁻, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isC-R^(4a); and R^(4a) is halo.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(5a) isN. In other embodiments, X^(5a) is C-R^(5a). In some embodiments, R^(5a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(5a) is H, D, F,or CH₃. In some embodiments, X^(5a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(5a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(5a) isC-R^(5a); and R^(5a) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(6a) isN. In other embodiments, X^(6a) is C-R^(6a). In some embodiments, R^(6a)is H, D, halo, or C₁-C₆ alkyl. In other embodiments, R^(6a) is H, D, F,or CH₃. In some embodiments, X^(6a) is N, C-H, C-D, C-(C₁-C₆ alkyl), orC-halo. In other embodiments, X^(6a) is N, C-H, C-D, C-CH₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(6a) isC-R^(6a); and R^(6a) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein R^(4b1)and R^(4b2) are each independently H or C₁-C₆ alkyl. In otherembodiments, R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl,or C₃-C₆ cycloalkyl. In other embodiments, R^(4b1) and R^(4b2) are eachindependently H or CH₃. In other embodiments, R^(4b1) and R^(4b2) areeach independently H, CH₃, CH₂CH₃, or cyclopropyl. In other embodiments,R^(4b1) is C₁-C₆ alkyl, and R^(4b2) is H. In other embodiments, R^(4b1)is H, and R^(4b2) is C₁-C₆ alkyl. In other embodiments, R^(4b1) is CH₃,and R^(4b2) is H. In other embodiments, R^(4b1) is H, and R^(4b2) isCH₃.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein R^(5b1)and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆ haloalkyl. Inother embodiments, R^(5b1) and R^(5b2) are each independently H, C₁-C₆alkyl, or C₁-C₆ haloalkyl. In other embodiments, R^(5b1) and R^(5b2) areeach independently H, CH₃, or CF₃. In other embodiments, R^(5b1) andR^(5b2) are each independently H, CH₃, CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CHF₂,CF₂CH₃, CH₂CF₃, or CF₃. In other embodiments, R^(5b1) is C₁-C₆ alkyl,and R^(5b2) is C₁-C₆ haloalkyl. In other embodiments, R^(5b1) is C₁-C₆haloalkyl, and R^(5b2) is C₁-C₆ alkyl. In other embodiments, R^(5b1) isCH₃, and R^(5b2) is CF₃. In other embodiments, R^(5b1) is CF₃, andR^(5b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein R^(2c) isOH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R^(2c) isOH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkylis optionally substituted with 1-2 halo. In other embodiments, R^(2c) isH. In other embodiments, R^(2c) is C₁-C₆ alkoxy. In other embodiments,R^(2c) is C₁-C₆ haloalkoxy. In other embodiments, R^(2c) is-L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkyl is optionallysubstituted with 1-2 halo. In other embodiments, R^(2c) is OH, OCH₃,OCD₃, OCH₂CH₃, or OCHF₂. In other embodiments, R^(2c) is H, F, CH₃,CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

In other embodiments, R^(2c) is OH. In other embodiments, R^(2c) isOCH₃. In other embodiments, R^(2c) is OCD₃. In other embodiments, R^(2c)is OCH₂CH₃. In other embodiments, R^(2c) is OCHF₂.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(3c) isN. In other embodiments, X^(3c) is C-R^(3c). In other embodiments,R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In otherembodiments, R^(3c) is H, CH₃, CH₂CH₃, CHF₂, CF₃, F, or Cl. In someembodiments, X^(3c) is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, orC-Cl.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(3c) isC-R^(3c); and R^(3c) is H, halo, or C₁-C₆ alkyl. In other embodiments,R^(3c) is halo. In other embodiments, R^(3c) is C₁-C₆ alkyl. In otherembodiments, R^(3c) is H, F, Cl, or CH₃. In other embodiments, R^(3c) isH. In other embodiments, R^(3c) is F. In other embodiments, R^(3c) isCl. In other embodiments, R^(3c) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4c) isN. In other embodiments, X^(4c) is C-R^(4c). In other embodiments,R^(4c) is H, halo, or C₁-C₆ haloalkyl. In other embodiments, R^(4c) isH, CHF₂, CF₃, or F. In some embodiments, X^(4c) is N, C-H, C-CHF₂,C-CF₃, or C-F.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4c) isC-R^(4c); and R^(4c) is halo. In other embodiments, R^(4c) is F.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(5c) isN. In other embodiments, X^(5c) is C-R^(5c). In other embodiments,R^(5c) is H or halo. In other embodiments, R^(5c) is H, D, or Cl. Insome embodiments, X^(5c) is N, C-H, C-D, or C-Cl.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(5c) isC-R^(5c); and R^(5c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(6c) isN. In other embodiments, X^(6c) is C-R^(6c). In other embodiments,R^(6c) is H or halo. In other embodiments, R^(6c) is H or F. In someembodiments, X^(6c) is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein R^(6c) isH.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN, C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; X^(4a) is N, N⁺-O⁻, C-H, orC-halo; X^(5a) is N, C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; X^(6a) is N,C-H, C-D, C-(C₁-C₆ alkyl), or C-halo; each R is H or CH₃; R^(4b1) andR^(4b2) are each independently H, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl;R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆haloalkyl; R^(2c) is OH, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or -L¹-L²-(C₃-C₆ cycloalkyl),wherein said cycloalkyl is optionally substituted with 1-2 halo; X^(3c)is C-R^(3c); R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X^(4c)is C-R^(4c); R^(4c) is H, halo, or C₁-C₆ haloalkyl; X^(5c) is C-R^(5c);R^(5c) is H or halo; X^(6c) is C-R^(6c); and R^(6c) is H or halo.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) and R^(4b2) areeach independently H or C₁-C₆ alkyl; R^(5b1) and R^(5b2) are eachindependently C₁-C₆ alkyl or C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, orC₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c).R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(2a) isN, C-H, C-D, C-CH₃, or C-F; X^(4a) is N, N⁺-O⁻, C-H, or C-F; X^(5a) isN, C-H, C-D, C-CH₃, or C-F; X^(6a) is N, C-H, C-D, C-CH₃, or C-F; each Ris H or CH₃; R^(4b1) and R^(4b2) are each independently H, CH₃, CH₂CH₃,or cyclopropyl; R^(5b1) and R^(5b2) are each independently H, CH₃,CH₂CH₃, CH(CH₃)₂, C(CH₃)₃, CHF₂, CF₂CH₃, CH₂CF₃, or CF₃; R^(2c) is H, F,CH₃, CH=CH₂, OH, OCH₃, OCD₃, OCH₂CH₃, OCH(CH₃)₂, OCHF₂,

X^(3c) is N, C-H, C-CH₃, C-CH₂CH₃, C-CHF₂, C-CF₃, C-F, or C-Cl; X^(4c)is N, C-H, C-CHF₂, C-CF₃, or C-F; X^(5c) is N, C-H, C-D, or C-Cl; andX^(6c) is N, C-H, or C-F.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) and R^(4b2) areeach independently H or CH₃; R^(5b1) and R^(5b2) are each independentlyH, CH₃, or CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c)is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c);R^(4c) is halo; X^(5c) is C-R^(5c). R^(5c) is H; X^(6c) is C-R^(6c); andR^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is C₁-C₆ alkyl;R^(4b2) is H; R^(5b1) is C₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is H; R^(4b2) isC₁-C₆ alkyl; R^(5b1) is C₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(4b1) is C₁-C₆ alkyl;R^(4b2) is H; R^(5b1) is C₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c) isH, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) isC-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is C₁-C₆haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl;R^(2c) is C₁-C₆ alkoxy or C₁-C₆ haloalkoxy; X^(3c) is C-R^(3c); R^(3c)is H, halo, or C₁-C₆ alkyl; X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c)is C-R^(5c); R^(5c) is H; X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CH₃; R^(5b2) isCF₃; R^(4b1) is CH₃; R^(4b2) is H; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c). R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CH₃; R^(5b2) isCF₃; R^(4b1) is H; R^(4b2) is CH₃; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c). R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CF₃; R^(5b2) isCH₃; R^(4b1) is CH₃; R^(4b2) is H; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c). R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C), or a pharmaceutically acceptable salt thereof, wherein X^(4a) isN; each R is H; X^(2a) is C-R^(2a); R^(2a) is H; X^(5a) is C-R^(5a);R^(5a) is H; X^(6a) is C-R^(6a); R^(6a) is H; R^(5b1) is CF₃; R^(5b2) isCH₃; R^(4b1) is H, and R^(4b2) is CH₃; R^(2c) is C₁-C₆ alkoxy or C₁-C₆haloalkoxy; X^(3c) is C-R^(3c); R^(3c) is H, halo, or C₁-C₆ alkyl;X^(4c) is C-R^(4c); R^(4c) is halo; X^(5c) is C-R^(5c); R^(5c) is H;X^(6c) is C-R^(6c); and R^(6c) is H.

In some embodiments, the invention relates to a compound of formula(I-C) (including any of the foregoing embodiments thereof), i.e., thecompound in non-salt form.

In some embodiments, the invention relates to a compound of formula(I-C-1)

or a pharmaceutically acceptable salt thereof, wherein:

-   X^(4a) is N, N⁺-O⁻, or C-R^(4a);-   each R is independently H or C₁-C₆ alkyl;-   R^(4a) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;-   R^(4b1) and R^(4b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆    haloalkyl;-   R^(5b1) and R^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆    haloalkyl;-   R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,    or C₁-C₆ haloalkoxy;-   R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and-   R^(4c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N. In other embodiments, X^(4a) is N⁺-O⁻. In other embodiments,X^(4a) is C-R^(4a). In some embodiments, R^(4a) is halo. In otherembodiments, X^(4a) is C-F.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein each Ris H. In other embodiments, each R is independently H or CH₃. In otherembodiments, N(R)₂ is NHCH₃.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein R^(4a)is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein R^(4b1)and R^(4b2) are each independently H or C₁-C₆ alkyl. In otherembodiments, R^(4b1) and R^(4b2) are each independently H or CH₃. Inother embodiments, R^(4b1) is C₁-C₆ alkyl, and R^(4b2) is H. In otherembodiments, R^(4b1) is H, and R^(4b2) is C₁-C₆ alkyl. In otherembodiments, R^(4b1) is CH₃, and R^(4b2) is H. In other embodiments,R^(4b1) is H, and R^(4b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein R^(5b1)and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆ haloalkyl. Inother embodiments, R^(5b1) and R^(5b2) are each independently H, CH₃, orCF₃. In other embodiments, R^(5b1) is C₁-C₆ alkyl, and R^(5b2) is C₁-C₆haloalkyl. In other embodiments, R^(5b1) is C₁-C₆ haloalkyl, and R^(5b2)is C₁-C₆ alkyl. In other embodiments, R^(5b1) is CH₃, and R^(5b2) isCF₃. In other embodiments, R^(5b1) is CF₃, and R^(5b2) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein R^(2c)is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy. In other embodiments, R^(2c)is C₁-C₆ alkoxy. In other embodiments, R^(2c) is C₁-C₆ haloalkoxy. Inother embodiments, R^(2c) is OH, OCH₃, OCD₃, OCH₂CH₃, or OCHF₂. In otherembodiments, R^(2c) is OH. In other embodiments, R^(2c) is OCH₃. Inother embodiments, R^(2c) is OCD₃. In other embodiments, R^(2c) isOCH₂CH₃. In other embodiments, R^(2c) is OCHF₂.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein R^(3c)is H, halo, or C₁-C₆ alkyl. In other embodiments, R^(3c) is halo. Inother embodiments, R^(3c) is C₁-C₆ alkyl. In other embodiments, R^(3c)is H, F, Cl, or CH₃. In other embodiments, R^(3c) is H. In otherembodiments, R^(3c) is F. In other embodiments, R^(3c) is Cl. In otherembodiments, R^(3c) is CH₃.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein R^(4c)is halo. In other embodiments, R^(4c) is F.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) and R^(4b2) are each independently H or C₁-C₆alkyl; R^(5b1) and R^(5b2) are each independently C₁-C₆ alkyl or C₁-C₆haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) and R^(4b2) are each independently H or CH₃;R^(5b1) and R^(5b2) are each independently H, CH₃, or CF₃; R^(2c) is OH,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl;and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is C₁-C₆ alkyl; R^(4b2) is H; R^(5b1) isC₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl; R^(5b1) isC₁-C₆ alkyl; R^(5b2) is C₁-C₆ haloalkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is C₁-C₆ alkyl; R^(4b2) is H; R^(5b1) isC₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is C₁-C₆ alkyl; R^(5b1) isC₁-C₆ haloalkyl; R^(5b2) is C₁-C₆ alkyl; R^(2c) is OH, C₁-C₆ alkoxy, orC₁-C₆ haloalkoxy; R^(3c) is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is CH₃; R^(4b2) is H; R^(5b1) is CH₃; R^(5b2)is CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H; R^(4b2) is CH₃; R^(5b1) is CH₃; R^(5b2)is CF₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is CH₃; R^(4b2) is H; R^(5b1) is CF₃; R^(5b2)is CH₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c) is H,halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1), or a pharmaceutically acceptable salt thereof, wherein X^(4a)is N; each R is H; R^(4b1) is H, and R^(4b2) is CH₃; R^(5b1) is CF₃;R^(5b2) is CH₃; R^(2c) is OH, C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy; R^(3c)is H, halo, or C₁-C₆ alkyl; and R^(4c) is halo.

In some embodiments, the invention relates to a compound of formula(I-C-1) (including any of the foregoing embodiments thereof), i.e., thecompound in non-salt form.

In some embodiments, the invention relates to a compound selected fromTable A or a pharmaceutically acceptable salt thereof. In otherembodiments, the invention relates to a compound selected from Table Ain non-salt form.

TABLE A Compound Structures and Names

4-((2R,3R,4R,5S)-3-(4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide4-((2S,3R,4R,5S)-3-(4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide

In some embodiments, the invention relates to a compound selected fromTable B or a pharmaceutically acceptable salt thereof. In otherembodiments, the invention relates to a compound selected from Table Bin non-salt form.

TABLE B Compound Structures and Names

In some embodiments, the invention relates to a compound selected fromTable C or a pharmaceutically acceptable salt thereof. In otherembodiments, the invention relates to a compound selected from Table Cin non-salt form.

TABLE C Compound Names(2R,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4R,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,SR)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,SR)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4,5,S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3R,4R,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3R,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3R,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3S,4R,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3R,4R,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3R,4S,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3S,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3R,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3S,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2,3R,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3S,4R,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,35,45,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(25,3R,4S,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3S,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3S,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2S,3S,4S,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3R,4R,SR)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3R,4R,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3R,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3S,4R,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3R,4R,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3R,4S,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3S,4R,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3R,4R,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3S,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3R,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3S,4R,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3S,4S,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3R,4S,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3S,4R,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3S,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3S,4S,5S)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3R,4S,SR)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,SR)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2R,,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide6-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide5-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide5-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2R,35,45,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide2-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2R,35,45,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide2-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide6-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide6-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide(2R,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2R,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(2S,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide5-deuterio-4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2R,35,45,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2S,35,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide5-deuterio-4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2R,35,45,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methyl-pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methyl-pyridine-2-carboxamide3-deuterio-4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2S,35,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide3-deuterio-4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2S,35,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide6-deuterio-4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,SR)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,35,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4S,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,35,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2,3S,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5,S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2R,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2R,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2R,3R,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2R,3S,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2S,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2R,3R,4S,5,S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2R,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2S,3R,4R,5,S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2S,3R,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2S,3S,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2R,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2S,3R,4S,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2S,3S,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2S,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(2S,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4R,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3R,4S,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4R,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4R,5R-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,SR)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,SR)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2R,3S,4S,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3R,4S,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4R,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide4-[[(2S,3S,4S,5S)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 1,Step 6. Such compound is considered to be a “compound of the invention,”as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 1,Step 6. Such compound is considered to be a “compound of the invention,”as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 1(Chiralpak AS-H column). Such compound is considered to be a “compoundof the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 1(Chiralpak AS-H column). Such compound is considered to be a “compoundof the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 2,Step 10. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 2,Step 10. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 3,Step 13. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 3,Step 13. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 3.Such compound is considered to be a “compound of the invention,” as thatterm is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 3.Such compound is considered to be a “compound of the invention,” as thatterm is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 1(Chiralpak AS-H column). Such compound is considered to be a “compoundof the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 1(Chiralpak AS-H column). Such compound is considered to be a “compoundof the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described inExample 4,Step 4. Such compound is considered to be a “compound of the invention,”as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 4,Step 4. Such compound is considered to be a “compound of the invention,”as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 4,Step 4 (Chiralpak AS-H column). Such compound is considered to be a“compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 4,Step 4 (Chiralpak AS-H column). Such compound is considered to be a“compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a mixtureof racemic diastereomers (epimeric at the 5-position) is separated bySFC as described in Example 6, Step 7. Such compound is considered to bea “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a mixtureof racemic diastereomers (epimeric at the 5-position) is separated bySFC as described in Example 6, Step 7. Such compound is considered to bea “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the third eluting isomer when a mixtureof racemic diastereomers (epimeric at the 5-position) is separated bySFC as described in Example 6, Step 7. Such compound is considered to bea “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the fourth eluting isomer when a mixtureof racemic diastereomers (epimeric at the 5-position) is separated bySFC as described in Example 6, Step 7. Such compound is considered to bea “compound of the invention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the first eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 7,Step 11. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof, wherein the compound hasthe absolute stereochemistry of the second eluting isomer when a racemicmixture of enantiomers is separated by SFC as described in Example 7,Step 11. Such compound is considered to be a “compound of theinvention,” as that term is used herein.

In some embodiments, the invention relates to a compound of formula

or a pharmaceutically acceptable salt thereof. Such compound isconsidered to be a “compound of the invention,” as that term is usedherein.

Solid Forms of Compounds of the Invention

In another aspect, the invention relates to a compound of the invention,or a pharmaceutically acceptable salt thereof, in solid form. In someembodiments, the compound of the invention, or pharmaceuticallyacceptable salt thereof, is in crystalline solid form.

Solid Forms of Compound 7

In some embodiments, the invention relates to a compound of formula

wherein the compound has the absolute stereochemistry of the secondeluting isomer when a racemic mixture of enantiomers is separated by SFCas described in Example 3, Step 13, wherein the compound is incrystalline solid form.

In some embodiments, the crystalline solid form is Form A.

In some embodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and19.0. In other embodiments, Form A is characterized by an XRPD patternhaving at least one, at least two, or at least three diffractions atangles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In otherembodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 7.3, 9.9, 13.9, 15.7,19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A ischaracterized by an XRPD pattern having at least one, at least two, atleast three, at least four, at least five, at least six, or at leastseven diffractions at angles (degrees 2 theta ± 0.2) of 7.3, 9.9, 13.9,15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A ischaracterized by an XRPD pattern substantially similar to FIG. 1 .

In some embodiments, Form A is characterized by a DSC thermogram havinga melting onset of 186° C. with a peak at 187° C.

In some embodiments, Form A is obtainable by crystallization frommethanol at 60° C.

In some embodiments, the crystalline solid form is Form B.

In some embodiments, Form B is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2,18.5, and 20.3. In other embodiments, Form B is characterized by an XRPDpattern having at least one, at least two, at least three, or at leastfour diffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2,18.5, and 20.3. In other embodiments, Form B is characterized by an XRPDpattern having diffractions at angles (degrees 2 theta ± 0.2) of 12.0,12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In otherembodiments, Form B is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, or at least nine diffractionsat angles (degrees 2 theta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4,18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B ischaracterized by an XRPD pattern having diffractions at angles (degrees2 theta ± 0.2) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9,17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0,24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, FormB is characterized by an XRPD pattern having at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, at least fourteen, at least fifteen, atleast sixteen, at least seventeen, at least eighteen, at least nineteen,at least twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, at least twenty-four, at least twenty-five, at leasttwenty-six, or at least twenty-seven diffractions at angles (degrees 2theta ± 0.2) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9,17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0,24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, FormB is characterized by an XRPD pattern substantially similar to FIG. 4 .

In some embodiments, Form B is characterized by a solid state ¹³C NMRspectrum having peaks at chemical shifts of 172.5, 172.1, 168.5, 168.3,168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5,80.2, 63.2, 44.3, 23.0, and 13.1 ppm. In some embodiments, Form B ischaracterized by a solid state ¹³C NMR spectrum substantially similar toFIG. 5 .

In some embodiments, Form B is characterized by a solid state ¹⁹F NMRspectrum having peaks at chemical shifts of -137.1 and -152.8 ppm. Insome embodiments, Form B is characterized by a solid state ¹⁹F NMRspectrum substantially similar to FIG. 6 .

In some embodiments, Form B is characterized by a DSC thermogram havinga melting onset of 182° C. with a peak at 183° C.

In some embodiments, Form B is characterized by an IR spectrum havingpeaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm⁻¹. In someembodiments, Form B is characterized by an IR spectrum substantiallysimilar to FIG. 9 .

In some embodiments, Form B is characterized by an orthorhombic crystalsystem, as determined by single-crystal X-ray analysis. In otherembodiments, Form B is characterized by a P2₁2₁2₁ space group, asdetermined by single-crystal X-ray analysis. In other embodiments, FormB is characterized by a unit cell, as determined by single-crystal X-rayanalysis, of the following dimensions: a=7.3929(2) Å; b=14.5827(4) Å;c=18.9312(6) Å; α=90°; β=90°; and γ=90°.

In some embodiments, Form B is obtainable by dissolving the compound inethyl acetate and then crystallizing the compound by adding n-heptane asan antisolvent. In other embodiments, Form B is obtainable by theprocedure described in Example 3.

In some embodiments, the invention relates to a compound of formula

wherein the compound is in crystalline solid form.

In some embodiments, the crystalline solid form is Form A.

In some embodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and19.0. In other embodiments, Form A is characterized by an XRPD patternhaving at least one, at least two, or at least three diffractions atangles (degrees 2 theta ± 0.2) of 9.9, 13.9, 15.7, and 19.0. In otherembodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 7.3, 9.9, 13.9, 15.7,19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A ischaracterized by an XRPD pattern having at least one, at least two, atleast three, at least four, at least five, at least six, or at leastseven diffractions at angles (degrees 2 theta ± 0.2) of 7.3, 9.9, 13.9,15.7, 19.0, 20.1, 20.3, and 25.4. In other embodiments, Form A ischaracterized by an XRPD pattern substantially similar to FIG. 1 .

In some embodiments, Form A is characterized by a DSC thermogram havinga melting onset of 186° C. with a peak at 187° C.

In some embodiments, Form A is obtainable by crystallization frommethanol at 60° C.

In some embodiments, the crystalline solid form is Form B.

In some embodiments, Form B is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2,18.5, and 20.3. In other embodiments, Form B is characterized by an XRPDpattern having at least one, at least two, at least three, or at leastfour diffractions at angles (degrees 2 theta ± 0.2) of 12.8, 14.1, 15.2,18.5, and 20.3. In other embodiments, Form B is characterized by an XRPDpattern having diffractions at angles (degrees 2 theta ± 0.2) of 12.0,12.8, 14.1, 15.2, 16.9, 18.4, 18.5, 18.7, 19.3, and 20.3. In otherembodiments, Form B is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, or at least nine diffractionsat angles (degrees 2 theta ± 0.2) of 12.0, 12.8, 14.1, 15.2, 16.9, 18.4,18.5, 18.7, 19.3, and 20.3. In other embodiments, Form B ischaracterized by an XRPD pattern having diffractions at angles (degrees2 theta ± 0.2) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9,17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0,24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, FormB is characterized by an XRPD pattern having at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, at least nine, at least ten, at least eleven, atleast twelve, at least thirteen, at least fourteen, at least fifteen, atleast sixteen, at least seventeen, at least eighteen, at least nineteen,at least twenty, at least twenty-one, at least twenty-two, at leasttwenty-three, at least twenty-four, at least twenty-five, at leasttwenty-six, or at least twenty-seven diffractions at angles (degrees 2theta ± 0.2) of 7.6, 9.2, 12.0, 12.8, 14.1, 15.1, 15.2, 16.2, 16.9,17.6, 18.4, 18.5, 18.7, 19.3, 20.3, 21.7, 22.0, 22.2, 22.9, 23.6, 24.0,24.2, 25.2, 26.9, 27.0, 27.4, 28.6, and 28.9. In other embodiments, FormB is characterized by an XRPD pattern substantially similar to FIG. 4 .

In some embodiments, Form B is characterized by a solid state ¹³C NMRspectrum having peaks at chemical shifts of 172.5, 172.1, 168.5, 168.3,168.0, 151.5, 148.3, 147.8, 127.7, 122.7, 116.6, 115.1, 110.6, 86.5,80.2, 63.2, 44.3, 23.0, and 13.1 ppm. In other embodiments, Form B ischaracterized by a solid state ¹³C NMR spectrum substantially similar toFIG. 5 .

In some embodiments, Form B is characterized by a solid state ¹⁹F NMRspectrum having peaks at chemical shifts of -137.1 and -152.8 ppm. Inother embodiments, Form B is characterized by a solid state ¹⁹F NMRspectrum substantially similar to FIG. 6 .

In some embodiments, Form B is characterized by a DSC thermogram havinga melting onset of 182° C. with a peak at 183° C.

In some embodiments, Form B is characterized by an IR spectrum havingpeaks at 3501, 3356, 1684, 1565, 1505, and 1122 cm⁻¹. In otherembodiments, Form B is characterized by an IR spectrum substantiallysimilar to FIG. 9 .

In some embodiments, Form B is characterized by an orthorhombic crystalsystem, as determined by single-crystal X-ray analysis. In otherembodiments, Form B is characterized by a P2₁2₁2₁ space group, asdetermined by single-crystal X-ray analysis. In other embodiments, FormB is characterized by a unit cell, as determined by single-crystal X-rayanalysis, of the following dimensions: a=7.3929(2) Å; b=14.5827(4) Å;c=18.9312(6) Å; α=90°; β=90°; and γ=90°.

In some embodiments, Form B is obtainable by dissolving the compound inethyl acetate and then crystallizing the compound by adding n-heptane asan antisolvent. In other embodiments, Form B is obtainable by theprocedure described in Example 3.

Solid Forms of Compound 9

In some embodiments, the invention relates to a compound of formula

wherein the compound is in crystalline solid form.

In some embodiments, the crystalline solid form is Form A.

In some embodiments, Form A is characterized by an orthorhombic crystalsystem, as determined by single-crystal X-ray analysis. In otherembodiments, Form A is characterized by an I222 space group, asdetermined by single-crystal X-ray analysis. In other embodiments, FormA is characterized by a unit cell, as determined by single-crystal X-rayanalysis, of the following dimensions: a=12.0172(5) Å; b=15.6682(6) Å;c=24.1406(11) Å; α=90°; β=90°; and γ=90°.

In some embodiments, Form A is obtainable by dissolving the compound ina 10/90 dichloromethane/dichloroethane solution, followed by vapordiffusion of pentane. In some embodiments, Form A is obtainable by theprocedure described in Example 3.

Solid Forms of Compound 11

In some embodiments, the invention relates to a compound of formula

wherein the compound is in crystalline solid form.

In some embodiments, the crystalline solid form is Form A.

In some embodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 10.1, 13.7, 14.1,16.3, and 20.0. In other embodiments, Form A is characterized by an XRPDpattern having at least one, at least two, at least three, or at leastfour diffractions at angles (degrees 2 theta ± 0.2) of 10.1, 13.7, 14.1,16.3, and 20.0. In other embodiments, Form A is characterized by an XRPDpattern having diffractions at angles (degrees 2 theta ± 0.2) of 7.3,10.1, 13.7, 14.1, 16.0, 16.3, 20.0, 20.4, 23.7, and 24.8. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, or at least nine diffractionsat angles (degrees 2 theta ± 0.2) of 7.3, 10.1, 13.7, 14.1, 16.0, 16.3,20.0, 20.4, 23.7, and 24.8. In other embodiments, Form A ischaracterized by an XRPD pattern having diffractions at angles (degrees2 theta ± 0.2) of 7.1, 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 17.6, 18.5,18.9, 20.0, 20.4, 21.5, 23.7, 24.8, 25.7, and 26.1. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, at least nine, at least ten,at least eleven, at least twelve, at least thirteen, at least fourteen,at least fifteen, or at least sixteen diffractions at angles (degrees 2theta ± 0.2) of 7.1, 7.3, 10.1, 13.7, 14.1, 16.0, 16.3, 17.6, 18.5,18.9, 20.0, 20.4, 21.5, 23.7, 24.8, 25.7, and 26.1. In otherembodiments, Form A is characterized by an XRPD pattern substantiallysimilar to FIG. 12 .

In some embodiments, Form A is obtainable by suspending the compound inwater. In other embodiments, Form A is obtainable by the proceduredescribed in Example 4.

In some embodiments, the crystalline solid form is Form B.

In some embodiments, Form B is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 6.8, 13.2, 16.1, 20.6,and 21.3. In other embodiments, Form B is characterized by an XRPDpattern having at least one, at least two, at least three, or at leastfour diffractions at angles (degrees 2 theta ± 0.2) of 6.8, 13.2, 16.1,20.6, and 21.3. In other embodiments, Form B is characterized by an XRPDpattern having diffractions at angles (degrees 2 theta ± 0.2) of 6.8,11.5, 13.2, 13.6, 14.4, 16.1, 16.3, 18.8, 20.6, and 21.3. In otherembodiments, Form B is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, or at least nine diffractionsat angles (degrees 2 theta ± 0.2) of 6.8, 11.5, 13.2, 13.6, 14.4, 16.1,16.3, 18.8, 20.6, and 21.3. In other embodiments, Form B ischaracterized by an XRPD pattern having diffractions at angles (degrees2 theta ± 0.2) of 6.8, 11.5, 13.2, 13.6, 14.4, 15.6, 16.1, 16.3, 17.6,18.0, 18.8, 19.4, 20.6, 21.3, 22.3, 23.3, 24.2, and 27.4. In otherembodiments, Form B is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, at least nine, at least ten,at least eleven, at least twelve, at least thirteen, at least fourteen,at least fifteen, at least sixteen, or at least seventeen diffractionsat angles (degrees 2 theta ± 0.2) of 6.8, 11.5, 13.2, 13.6, 14.4, 15.6,16.1, 16.3, 17.6, 18.0, 18.8, 19.4, 20.6, 21.3, 22.3, 23.3, 24.2, and27.4. In other embodiments, Form B is characterized by an XRPD patternsubstantially similar to FIG. 13 .

In some embodiments, Form A is characterized by a monoclinic crystalsystem, as determined by single-crystal X-ray analysis. In otherembodiments, Form A is characterized by a P2₁ space group, as determinedby single-crystal X-ray analysis. In other embodiments, Form A ischaracterized by a unit cell, as determined by single-crystal X-rayanalysis, of the following dimensions: a=12.0863(2) Å; b=7.48310(10) Å;c=23.9904(4) Å; α=90°; β=90.0130(10)°; and γ=90°.

In some embodiments, Form B is obtainable by recrystallization fromacetonitrile. In other embodiments, Form B is obtainable by theprocedure described in Example 4.

Solid Form of Compound 19

In some embodiments, the invention relates to a compound of formula

wherein the compound is in crystalline solid form.

In some embodiments, the crystalline solid form is Form A.

In some embodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 13.7, 15.2, and 18.2.In other embodiments, Form A is characterized by an XRPD pattern havingat least one or at least two diffractions at angles (degrees 2 theta ±0.2) of 13.7, 15.2, and 18.2. In other embodiments, Form A ischaracterized by an XRPD pattern having diffractions at angles (degrees2 theta ± 0.2) of 13.7, 15.2, 18.2, 18.3, 20.8, and 23.8. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, or at least fivediffractions at angles (degrees 2 theta ± 0.2) of 13.7, 15.2, 18.2,18.3, 20.8, and 23.8. In other embodiments, Form A is characterized byan XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5, 23.8, and 25.8. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, or at least eight diffractions at angles(degrees 2 theta ± 0.2) of 13.7, 14.3, 15.2, 18.2, 18.3, 20.8, 22.5,23.8, and 25.8. In other embodiments, Form A is characterized by an XRPDpattern having diffractions at angles (degrees 2 theta ± 0.2) of 6.8,13.7, 14.3, 15.2, 16.1, 18.2, 18.3, 19.1, 20.6, 20.8, 22.5, 23.8, 24.0,25.8, 26.3, and 26.6. In other embodiments, Form A is characterized byan XRPD pattern having at least one, at least two, at least three, atleast four, at least five, at least six, at least seven, at least eight,at least nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, or at least fifteen diffractions at angles(degrees 2 theta ± 0.2) of 6.8, 13.7, 14.3, 15.2, 16.1, 18.2, 18.3,19.1, 20.6, 20.8, 22.5, 23.8, 24.0, 25.8, 26.3, and 26.6. In otherembodiments, Form A is characterized by an XRPD pattern substantiallysimilar to FIG. 15 .

In some embodiments, Form A is characterized by a solid state ¹³C NMRspectrum having peaks at chemical shifts of 171.4, 141.6, 118.0, 112.2,23.0, and 11.6 ppm. In other embodiments, Form A is characterized by asolid state ¹³C NMR spectrum having peaks at chemical shifts of 171.4,164.2, 151.8, 149.5, 148.4, 146.6, 144.0, 141.6, 138.7, 126.2, 123.8,118.0, 112.2, 86.4, 78.8, 63.3, 47.6, 43.8, 23.0, and 11.6 ppm. In otherembodiments, Form A is characterized by a solid state ¹³C NMR spectrumsubstantially similar to FIG. 16 .

In some embodiments, Form A is characterized by a solid state ¹⁹F NMRspectrum having peaks at chemical shifts of -74.6, -141.5, and -154.6ppm. In other embodiments, Form A is characterized by a solid state ¹⁹FNMR spectrum substantially similar to FIG. 17 .

In some embodiments, Form A is characterized by a monoclinic crystalsystem, as determined by single-crystal X-ray analysis. In otherembodiments, Form A is characterized by a P2₁ space group, as determinedby single-crystal X-ray analysis. In other embodiments, Form A ischaracterized by a unit cell, as determined by single-crystal X-rayanalysis, of the following dimensions: a=11.2266(3) Å; b=7.3948(2) Å;c=13.1432(4) Å; α=90°; β=100.3980(1)°; and γ=90°.

In some embodiments, Form A is obtainable by precipitation from methanolvia addition of heptane antisolvent. In other embodiments, Form A isobtainable from a suspension of the compound in ethanol, acetonitrile,and water by lyophilization. In other embodiments, Form A is obtainableby dissolving the compound in methanol and allowing slow diffusion ofheptane antisolvent. In other embodiments, Form A is obtainable by theprocedure described in Example 5.

Solid Form of Compound 22

In some embodiments, the invention relates to a compound of formula

wherein the compound has the absolute stereochemistry of the thirdeluting isomer when a mixture of racemic diastereomers (epimeric at the5-position) is separated by SFC as described in Example 6, Step 7,wherein the compound is in crystalline solid form.

In some embodiments, the crystalline solid form is Form A.

In some embodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 9.2, 10.4, and 15.7.In other embodiments, Form A is characterized by an XRPD pattern havingat least one or at least two diffractions at angles (degrees 2 theta ±0.2) of 9.2, 10.4, and 15.7. In other embodiments, Form A ischaracterized by an XRPD pattern having diffractions at angles (degrees2 theta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 15.7, and 18.4. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, or at least fivediffractions at angles (degrees 2 theta ± 0.2) of 7.7, 9.2, 10.4, 12.9,15.7, and 18.4. In other embodiments, Form A is characterized by an XRPDpattern having diffractions at angles (degrees 2 theta ± 0.2) of 7.7,9.2, 10.4, 12.9, 15.7, 18.4, 19.8, 21.7, and 24.0. In other embodiments,Form A is characterized by an XRPD pattern having at least one, at leasttwo, at least three, at least four, at least five, at least six, atleast seven, or at least eight diffractions at angles (degrees 2 theta ±0.2) of 7.7, 9.2, 10.4, 12.9, 15.7, 18.4, 19.8, 21.7, and 24.0. In otherembodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 7.7, 9.2, 10.4, 12.9,13.8, 14.7, 15.7, 16.1, 18.4, 19.8, 21.7, 22.3, and 24.0. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, at least nine, at least ten,at least eleven, or at least twelve diffractions at angles (degrees 2theta ± 0.2) of 7.7, 9.2, 10.4, 12.9, 13.8, 14.7, 15.7, 16.1, 18.4,19.8, 21.7, 22.3, and 24.0. In other embodiments, Form A ischaracterized by an XRPD pattern substantially similar to FIG. 19 .

In some embodiments, Form A is characterized by a solid state ¹³C NMRspectrum having peaks at chemical shifts of 167.7, 126.0, 115.9, 43.5,and 20.3 ppm. In other embodiments, Form A is characterized by a solidstate ¹³C NMR spectrum having peaks at chemical shifts of 172.6, 167.7,158.7, 156.8, 151.8, 148.7, 128.6, 126.0, 115.9, 113.1, 112.3, 88.0,85.5, 62.0, 60.5, 55.6, 43.5, 37.7, 29.6, 21.1, and 20.3 ppm. In otherembodiments, Form A is characterized by a solid state ¹³C NMR spectrumsubstantially similar to FIG. 20 .

In some embodiments, Form A is characterized by a solid state ¹⁹F NMRspectrum having peaks at chemical shifts of -82.2, -83.1, -111.7, and-114.4 ppm. In other embodiments, Form A is characterized by a solidstate ¹⁹F NMR spectrum substantially similar to FIG. 21 .

In some embodiments, Form A is obtainable by slow evaporation of a 1:12-methyltetrahydrofuran/heptane solution. In other embodiments, Form Ais obtainable by the procedure described in Example 6.

Solid Form of Compound 23

In some embodiments, the invention relates to a compound of formula

wherein the compound is in crystalline solid form.

In some embodiments, the crystalline solid form is Form A.

In some embodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 17.2, 19.3, and 22.3.In other embodiments, Form A is characterized by an XRPD pattern havingat least one or at least two diffractions at angles (degrees 2 theta ±0.2) of 17.2, 19.3, and 22.3. In other embodiments, Form A ischaracterized by an XRPD pattern having diffractions at angles (degrees2 theta ± 0.2) of 14.2, 15.8, 17.2, 19.3, 22.3, and 30.6. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, or at least fivediffractions at angles (degrees 2 theta ± 0.2) of 14.2, 15.8, 17.2,19.3, 22.3, and 30.6. In other embodiments, Form A is characterized byan XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of12.2, 14.2, 15.8, 17.2, 19.3, 22.3, 25.0, 25.1, and 30.6. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, or at least eight diffractions at angles(degrees 2 theta ± 0.2) of 12.2, 14.2, 15.8, 17.2, 19.3, 22.3, 25.0,25.1, and 30.6. In other embodiments, Form A is characterized by an XRPDpattern having diffractions at angles (degrees 2 theta ± 0.2) of 11.3,12.2, 13.2, 14.2, 15.2, 15.8, 16.6, 17.2, 19.3, 21.1, 22.3, 22.8, 23.7,24.6, 25.0, 25.1, 25.9, 27.1, 27.9, 30.6, 34.4, and 39.4. In otherembodiments, Form A is characterized by an XRPD pattern having at leastone, at least two, at least three, at least four, at least five, atleast six, at least seven, at least eight, at least nine, at least ten,at least eleven, at least twelve, at least thirteen, at least fourteen,at least fifteen, at least sixteen, at least seventeen, at leasteighteen, at least nineteen, at least twenty, or at least twenty-onediffractions at angles (degrees 2 theta ± 0.2) of 11.3, 12.2, 13.2,14.2, 15.2, 15.8, 16.6, 17.2, 19.3, 21.1, 22.3, 22.8, 23.7, 24.6, 25.0,25.1, 25.9, 27.1, 27.9, 30.6, 34.4, and 39.4. In other embodiments, FormA is characterized by an XRPD pattern substantially similar to FIG. 22 .

In some embodiments, Form A is characterized by a solid state ¹³C NMRspectrum having peaks at chemical shifts of 171.1, 149.3, 123.3, 41.6,and 20.0 ppm. In other embodiments, Form A is characterized by a solidstate ¹³C NMR spectrum having peaks at chemical shifts of 171.1, 166.7,156.8, 155.5, 151.9, 149.3, 147.3, 131.5, 123.3, 119.0, 114.2, 112.8,86.0, 85.0, 61.7, 61.0, 44.4, 41.6, and 20.0 ppm. In other embodiments,Form A is characterized by a solid state ¹³C NMR spectrum substantiallysimilar to FIG. 23 .

In some embodiments, Form A is characterized by a solid state ¹⁹F NMRspectrum having peaks at chemical shifts of -78.2, -113.5, and -115.1ppm. In other embodiments, Form A is characterized by a solid state ¹⁹FNMR spectrum substantially similar to FIG. 24 .

In some embodiments, Form A is characterized by a monoclinic crystalsystem, as determined by single-crystal X-ray analysis. In otherembodiments, Form A is characterized by a P2₁ space group, as determinedby single-crystal X-ray analysis. In other embodiments, Form A ischaracterized by a unit cell, as determined by single-crystal X-rayanalysis, of the following dimensions: a=7.8661(3) Å; b=7.9167(3) Å;c=16.8777(7) Å; α=90°; β=98.487(2)°; and γ=90°.

In some embodiments, Form A is obtainable by slow evaporation of a 1: 12-methyltetrahydrofuran/heptane solution. In other embodiments, Form Ais obtainable by dissolving the compound in methanol and allowing slowdiffusion of heptane vapor. In other embodiments, Form A is obtainableby the procedure described in Example 6.

Solid Form of Compound 25

In some embodiments, the invention relates to a compound of formula

wherein the compound has the absolute stereochemistry of the secondeluting isomer when a racemic mixture of enantiomers is separated by SFCas described in Example 7, Step 11, wherein the compound is incrystalline solid form.

In some embodiments, the crystalline solid form is Form A.

In some embodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 6.8, 7.9, and 13.8. Inother embodiments, Form A is characterized by an XRPD pattern having atleast one or at least two diffractions at angles (degrees 2 theta ± 0.2)of 6.8, 7.9, and 13.8. In other embodiments, Form A is characterized byan XRPD pattern having diffractions at angles (degrees 2 theta ± 0.2) of6.8, 7.9, 11.0, 13.7, 13.8, and 27.4. In other embodiments, Form A ischaracterized by an XRPD pattern having at least one, at least two, atleast three, at least four, or at least five diffractions at angles(degrees 2 theta ± 0.2) of 6.8, 7.9, 11.0, 13.7, 13.8, and 27.4. Inother embodiments, Form A is characterized by an XRPD pattern havingdiffractions at angles (degrees 2 theta ± 0.2) of 6.8, 7.9, 11.0, 13.7,13.8, 15.9, 16.3, 23.2, and 27.4. In other embodiments, Form A ischaracterized by an XRPD pattern having at least one, at least two, atleast three, at least four, at least five, at least six, at least seven,or at least eight diffractions at angles (degrees 2 theta ± 0.2) of 6.8,7.9, 11.0, 13.7, 13.8, 15.9, 16.3, 23.2, and 27.4. In other embodiments,Form A is characterized by an XRPD pattern having diffractions at angles(degrees 2 theta ± 0.2) of 3.2, 6.8, 7.9, 11.0, 11.8, 13.7, 13.8, 15.1,15.9, 16.3, 17.5, 18.6, 19.0, 19.5, 21.6, 21.9, 23.2, 27.0, 27.4, 29.4,and 30.3. In other embodiments, Form A is characterized by an XRPDpattern having at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, atleast nine, at least ten, at least eleven, at least twelve, at leastthirteen, at least fourteen, at least fifteen, at least sixteen, atleast seventeen, at least eighteen, at least nineteen, or at leasttwenty diffractions at angles (degrees 2 theta ± 0.2) of 3.2, 6.8, 7.9,11.0, 11.8, 13.7, 13.8, 15.1, 15.9, 16.3, 17.5, 18.6, 19.0, 19.5, 21.6,21.9, 23.2, 27.0, 27.4, 29.4, and 30.3. In other embodiments, Form A ischaracterized by an XRPD pattern substantially similar to FIG. 26 .

In some embodiments, Form A is obtainable by slow evaporation of a 1:12-methyltetrahydrofuran/heptane solution. In other embodiments, Form Ais obtainable by the procedure described in Example 7.

Salts, Compositions, Uses, Formulation, Administration and AdditionalAgents Pharmaceutically Acceptable Salts and Compositions

As discussed herein, the invention provides compounds, andpharmaceutically acceptable salts thereof, that are inhibitors ofvoltage-gated sodium channels, and thus the present compounds, andpharmaceutically acceptable salts thereof, are useful for the treatmentof diseases, disorders, and conditions including, but not limited tochronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain(e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain),visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, pathological cough, or cardiac arrhythmia. Accordingly, inanother aspect of the invention, pharmaceutical compositions areprovided, wherein these compositions comprise a compound as describedherein, or a pharmaceutically acceptable salt thereof, and optionallycomprise a pharmaceutically acceptable carrier, adjuvant or vehicle. Incertain embodiments, these compositions optionally further comprise oneor more additional therapeutic agents. In some embodiments, theadditional therapeutic agent is a sodium channel inhibitor.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” of a compound of this inventionincludes any non-toxic salt that, upon administration to a recipient, iscapable of providing, either directly or indirectly, a compound of thisinvention or an inhibitorily active metabolite or residue thereof. Thesalt may be in pure form, in a mixture (e.g., solution, suspension, orcolloid) with one or more other substances, or in the form of a hydrate,solvate, or co-crystal. As used herein, the term “inhibitorily activemetabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

As described herein, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington’s PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical compositioncomprising a compound of the invention, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention features a pharmaceutical compositioncomprising a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers or vehicles.

Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject a compound of the invention or a pharmaceutically acceptablesalt thereof or a pharmaceutical composition thereof. In another aspect,the voltage-gated sodium channel is Na_(v)1.8.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain (e.g., bunionectomypain, herniorrhaphy pain or abdominoplasty pain), visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, or cardiac arrhythmia comprising administering aneffective amount of a compound of the invention, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, postsurgical pain, bunionectomy pain,herniorrhaphy pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, or cardiac arrhythmia comprising administering aneffective amount of a compound of the invention, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn’s disease pain orinterstitial cystitis pain wherein said method comprises administeringan effective amount of a compound of the invention, a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the neuropathic pain comprises post-herpeticneuralgia, small fiber neuropathy or idiopathic small-fiber neuropathy.As used herein, the phrase “idiopathic small-fiber neuropathy” shall beunderstood to include any small fiber neuropathy. In some aspects, theneuropathic pain comprises diabetic neuropathy.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain, whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma;traumatic neuroma; Morton’s neuroma; nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury; complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia; post spinal cordinjury pain, small fiber neuropathy, idiopathic small-fiber neuropathy,idiopathic sensory neuropathy or trigeminal autonomic cephalalgiawherein said method comprises administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the musculoskeletal pain comprisesosteoarthritis pain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain, whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain wherein said method comprisesadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain or vulvodyniawherein said method comprises administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain wherein saidmethod comprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain, whereinidiopathic pain comprises fibromyalgia pain wherein said methodcomprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of pathological cough wherein saidmethod comprises administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the acute pain comprises acute post-operativepain.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of postsurgical pain (e.g.,bunionectomy pain, herniorrhaphy pain or abdominoplasty pain) comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of bunionectomy pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of herniorrhaphy pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of abdominoplasty pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of visceral pain comprisingadministering an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In some aspects, the visceral pain comprises visceral pain fromabdominoplasty.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of a neurodegenerative diseasecomprising administering an effective amount of a compound of theinvention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof. In some aspects, theneurodegenerative disease comprises multiple sclerosis. In some aspects,the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

In yet another aspect, the invention features a method wherein thesubject is treated with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith an effective amount of the compound, pharmaceutically acceptablesalt or pharmaceutical composition. In some embodiments, the additionaltherapeutic agent is a sodium channel inhibitor.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a biological sample comprisingcontacting the biological sample with an effective amount of a compoundof the invention, a pharmaceutically acceptable salt thereof or apharmaceutical composition thereof. In another aspect, the voltage-gatedsodium channel is Na_(V)1.8.

In another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain, chronic pain,neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, pathological cough,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head pain, neck pain,severe pain, intractable pain, nociceptive pain, breakthrough pain,postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain orabdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumaticbrain injury, amyotrophic lateral sclerosis, stress induced angina,exercise induced angina, palpitations, hypertension, or abnormalgastro-intestinal motility, comprising administering an effective amountof a compound of the invention, a pharmaceutically acceptable saltthereof or a pharmaceutical composition thereof.

In another aspect, the invention features a method of treating orlessening the severity in a subject of femur cancer pain; non-malignantchronic bone pain; rheumatoid arthritis; osteoarthritis; spinalstenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache; cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Toothneuropathy; hereditary sensory neuropathy; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury pain; exercise pain; acute visceral pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatorypain, burn pain, trauma pain; acute intermittent pain, endometriosis;acute herpes zoster pain; sickle cell anemia; acute pancreatitis;breakthrough pain; orofacial pain; sinusitis pain; dental pain; multiplesclerosis (MS) pain; pain in depression; leprosy pain; Behcet’s diseasepain; adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painfullegs and moving toes; Haglund syndrome; erythromelalgia pain; Fabry’sdisease pain; bladder and urogenital disease; urinary incontinence,pathological cough; hyperactive bladder; painful bladder syndrome;interstitial cystitis (IC); prostatitis; complex regional pain syndrome(CRPS), type I, complex regional pain syndrome (CRPS) type II;widespread pain, paroxysmal extreme pain, pruritus, tinnitus, orangina-induced pain, comprising administering an effective amount of acompound of the invention, a pharmaceutically acceptable salt thereof ora pharmaceutical composition thereof.

Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use as a medicament.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of inhibiting a voltage-gated sodiumchannel in a subject. In another aspect, the voltage-gated sodiumchannel is Na_(v)1.8.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of chronic pain, gut pain, neuropathic pain, musculoskeletalpain, acute pain, inflammatory pain, cancer pain, idiopathic pain,postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain orabdominoplasty pain), visceral pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, pathological cough, orcardiac arrhythmia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of chronic pain, gut pain, neuropathic pain, musculoskeletalpain, acute pain, inflammatory pain, cancer pain, idiopathic pain,postsurgical pain, bunionectomy pain, herniorrhaphy pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence, or cardiacarrhythmia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of gut pain, wherein gut pain comprises inflammatory boweldisease pain, Crohn’s disease pain or interstitial cystitis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of neuropathic pain. In some aspects, the neuropathic paincomprises post-herpetic neuralgia, small fiber neuropathy or idiopathicsmall-fiber neuropathy. As used herein, the phrase “idiopathicsmall-fiber neuropathy” shall be understood to include any small fiberneuropathy. In some aspects, the neuropathic pain comprises diabeticneuropathy.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of neuropathic pain, wherein neuropathic pain comprisespost-herpetic neuralgia, diabetic neuralgia, painful HIV-associatedsensory neuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma; traumatic neuroma;Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathicsensory neuropathy or trigeminal autonomic cephalalgia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of musculoskeletal pain. In some aspects, the musculoskeletalpain comprises osteoarthritis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of musculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of inflammatory pain, wherein inflammatory pain comprisesrheumatoid arthritis pain or vulvodynia.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of inflammatory pain, wherein inflammatory pain comprisesrheumatoid arthritis pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of idiopathic pain, wherein idiopathic pain comprisesfibromyalgia pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of pathological cough.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of acute pain. In some aspects, the acute pain comprises acutepost-operative pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of postsurgical pain (e.g., bunionectomy pain, herniorrhaphypain or abdominoplasty pain).

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of bunionectomy pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of herniorrhaphy pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of abdominoplasty pain.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of visceral pain. In some aspects, the visceral pain comprisesvisceral pain from abdominoplasty.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of a neurodegenerative disease. In some aspects, theneurodegenerative disease comprises multiple sclerosis. In some aspects,the neurodegenerative disease comprises Pitt Hopkins Syndrome (PTHS).

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method wherein the subject is treated with one ormore additional therapeutic agents administered concurrently with, priorto, or subsequent to treatment with an effective amount of the compound,pharmaceutically acceptable salt or pharmaceutical composition. In someembodiments, the additional therapeutic agent is a sodium channelinhibitor.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of inhibiting a voltage-gated sodiumchannel in a biological sample comprising contacting the biologicalsample with an effective amount of a compound of the invention, apharmaceutically acceptable salt thereof or a pharmaceutical compositionthereof. In another aspect, the voltage-gated sodium channel isNa_(v)1.8.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of acute pain, chronic pain, neuropathic pain, inflammatorypain, arthritis, migraine, cluster headaches, trigeminal neuralgia,herpetic neuralgia, general neuralgias, epilepsy, epilepsy conditions,neurodegenerative disorders, psychiatric disorders, anxiety, depression,bipolar disorder, myotonia, arrhythmia, movement disorders,neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowelsyndrome, incontinence, pathological cough, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head pain, neck pain, severe pain,intractable pain, nociceptive pain, breakthrough pain, postsurgical pain(e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain),cancer pain, stroke, cerebral ischemia, traumatic brain injury,amyotrophic lateral sclerosis, stress induced angina, exercise inducedangina, palpitations, hypertension, or abnormal gastro-intestinalmotility.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for use in a method of treating or lessening the severity in asubject of femur cancer pain; non-malignant chronic bone pain;rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lowback pain; myofascial pain syndrome; fibromyalgia; temporomandibularjoint pain; chronic visceral pain, abdominal pain; pancreatic pain; IBSpain; chronic and acute headache pain; migraine; tension headache;cluster headaches; chronic and acute neuropathic pain, post-herpeticneuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminalneuralgia; Charcot-Marie-Tooth neuropathy; hereditary sensoryneuropathy; peripheral nerve injury; painful neuromas; ectopic proximaland distal discharges; radiculopathy; chemotherapy induced neuropathicpain; radiotherapy-induced neuropathic pain; post-mastectomy pain;central pain; spinal cord injury pain; post-stroke pain; thalamic pain;complex regional pain syndrome; phantom pain; intractable pain; acutepain, acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury pain; exercisepain; acute visceral pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; chest pain, cardiac pain; pelvic pain,renal colic pain, acute obstetric pain, labor pain; cesarean sectionpain; acute inflammatory pain, burn pain, trauma pain; acuteintermittent pain, endometriosis; acute herpes zoster pain; sickle cellanemia; acute pancreatitis; breakthrough pain; orofacial pain; sinusitispain; dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet’s disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry’s disease pain; bladder and urogenitaldisease; urinary incontinence, pathological cough; hyperactive bladder;painful bladder syndrome; interstitial cystitis (IC); prostatitis;complex regional pain syndrome (CRPS), type I, complex regional painsyndrome (CRPS) type II; widespread pain, paroxysmal extreme pain,pruritus, tinnitus, or angina-induced pain.

Manufacture of Medicaments

In another aspect, the invention provides the use of a compound of theinvention, or a pharmaceutically acceptable salt or pharmaceuticalcomposition thereof, for the manufacture of a medicament.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in inhibiting a voltage-gated sodium channel. In another aspect,the voltage-gated sodium channel is Na_(v)1.8.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of chronicpain, gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, postsurgical pain(e.g., bunionectomy pain, herniorrhaphy pain or abdominoplasty pain),visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome,incontinence, pathological cough, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of chronicpain, gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, postsurgical pain,bunionectomy pain, herniorrhaphy pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of the compound,pharmaceutically acceptable salt, or pharmaceutical compositiondescribed herein for the manufacture of a medicament for use in treatingor lessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn’s disease pain orinterstitial cystitis pain.

In yet another aspect, the invention provides a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofneuropathic pain. In some aspects, the neuropathic pain comprisespost-herpetic neuralgia, small fiber neuropathy or idiopathicsmall-fiber neuropathy. In some aspects, the neuropathic pain comprisesdiabetic neuropathy.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in a treating or lessening the severity in a subject ofneuropathic pain, wherein neuropathic pain comprises post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma; traumatic neuroma;Morton’s neuroma; nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain; nerve avulsion injury,brachial plexus avulsion injury; complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia; post spinal cord injury pain,small fiber neuropathy, idiopathic small-fiber neuropathy, idiopathicsensory neuropathy or trigeminal autonomic neuropathy.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofmusculoskeletal pain. In some aspects the musculoskeletal pain comprisesosteoarthritis pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofmusculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain or vulvodynia.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of idiopathicpain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofpathological cough.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of acutepain. In some aspects, the acute pain comprises acute post-operativepain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofpostsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain orabdominoplasty pain).

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofbunionectomy pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofherniorrhaphy pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject ofabdominoplasty pain.

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity in a subject of visceralpain. In some aspects, the visceral pain comprises visceral pain fromabdominoplasty.

In another aspect, the invention features a compound of the invention,or a pharmaceutically acceptable salt or pharmaceutical compositionthereof, for the manufacture of a medicament for use in treating orlessening the severity in a subject of a neurodegenerative disease. Insome aspects, the neurodegenerative disease comprises multiplesclerosis. In some aspects, the neurodegenerative disease comprises PittHopkins Syndrome (PTHS).

In yet another aspect, the invention provides the use of a compound ofthe invention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in combination with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith the compound or pharmaceutical composition. In some embodiments,the additional therapeutic agent is a sodium channel inhibitor.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity of acute pain, chronicpain, neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, bipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, pathological cough,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head pain, neck pain,severe pain, intractable pain, nociceptive pain, breakthrough pain,postsurgical pain (e.g., bunionectomy pain, herniorrhaphy pain orabdominoplasty pain), cancer pain, stroke, cerebral ischemia, traumaticbrain injury, amyotrophic lateral sclerosis, stress induced angina,exercise induced angina, palpitations, hypertension, or abnormalgastro-intestinal motility.

In another aspect, the invention provides the use of a compound of theinvention, a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof for the manufacture of a medicamentfor use in treating or lessening the severity of femur cancer pain;non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;spinal stenosis; neuropathic low back pain; myofascial pain syndrome;fibromyalgia; temporomandibular joint pain; chronic visceral pain,abdominal pain; pancreatic pain; IBS pain; chronic and acute headachepain; migraine; tension headache; cluster headaches; chronic and acuteneuropathic pain, post-herpetic neuralgia; diabetic neuropathy;HIV-associated neuropathy; trigeminal neuralgia; Charcot-Marie-Toothneuropathy; hereditary sensory neuropathy; peripheral nerve injury;painful neuromas; ectopic proximal and distal discharges; radiculopathy;chemotherapy induced neuropathic pain; radiotherapy-induced neuropathicpain; post-mastectomy pain; central pain; spinal cord injury pain;post-stroke pain; thalamic pain; complex regional pain syndrome; phantompain; intractable pain; acute pain, acute post-operative pain; acutemusculoskeletal pain; joint pain; mechanical low back pain; neck pain;tendonitis; injury pain; exercise pain; acute visceral pain;pyelonephritis; appendicitis; cholecystitis; intestinal obstruction;hernias; chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain; acute inflammatory,burn pain, trauma pain; acute intermittent pain, endometriosis; acuteherpes zoster pain; sickle cell anemia; acute pancreatitis; breakthroughpain; orofacial pain; sinusitis pain; dental pain; multiple sclerosis(MS) pain; pain in depression; leprosy pain; Behcet’s disease pain;adiposis dolorosa; phlebitic pain; Guillain-Barre pain; painful legs andmoving toes; Haglund syndrome; erythromelalgia pain; Fabry’s diseasepain; bladder and urogenital disease; urinary incontinence; pathologicalcough; hyperactive bladder; painful bladder syndrome; interstitialcystitis (IC); prostatitis; complex regional pain syndrome (CRPS) typeI; complex regional pain syndrome (CRPS) type II; widespread pain,paroxysmal extreme pain, pruritus, tinnitus, or angina-induced pain.

Administration of Pharmaceutically Acceptable Salts and Compositions.

In certain embodiments of the invention an “effective amount” of acompound of the invention, a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof is that amount effective fortreating or lessening the severity of one or more of the conditionsrecited above.

The compounds, salts, and compositions, according to the method of theinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of the pain or non-pain diseases recited herein. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of thecondition, the particular agent, its mode of administration, and thelike. The compounds, salts, and compositions of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of agent appropriate for thesubject to be treated. It will be understood, however, that the totaldaily usage of the compounds, salts, and compositions of the inventionwill be decided by the attending physician within the scope of soundmedical judgment. The specific effective dose level for any particularsubject or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound or salt employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thesubject; the time of administration, route of administration, and rateof excretion of the specific compound or salt employed; the duration ofthe treatment; drugs used in combination or coincidental with thespecific compound or salt employed, and like factors well known in themedical arts. The term “subject” or “patient,” as used herein, means ananimal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the condition being treated. Incertain embodiments, the compound, salts, and compositions of theinvention may be administered orally or parenterally at dosage levels ofabout 0.001 mg/kg to about 100 mg/kg, or about 0.01 mg/kg to about 50mg/kg, of subject body weight per day, one or more times a day,effective to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compound orsalt, the liquid dosage forms may contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer’s solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of the compounds of the invention, it isoften desirable to slow the absorption of the compounds fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compound or salt ofthis invention with suitable non-irritating excipients or carriers suchas cocoa butter, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound or salt is mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and silicic acid, b) binders such as, forexample, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such asglycerol, d) disintegrating agents such as agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates, and sodiumcarbonate, e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compound or salt can also be in microencapsulated form withone or more excipients as noted above. The solid dosage forms oftablets, dragees, capsules, pills, and granules can be prepared withcoatings and shells such as enteric coatings, release controllingcoatings and other coatings well known in the pharmaceutical formulatingart. In such solid dosage forms the active compound or salt may beadmixed with at least one inert diluent such as sucrose, lactose orstarch. Such dosage forms may also comprise, as is normal practice,additional substances other than inert diluents, e.g., tabletinglubricants and other tableting aids such a magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets and pills,the dosage forms may also comprise buffering agents. They may optionallycontain opacifying agents and can also be of a composition that theyrelease the active ingredient(s) only, or preferentially, in a certainpart of the intestinal tract, optionally, in a delayed manner. Examplesof embedding compositions that can be used include polymeric substancesand waxes.

Dosage forms for topical or transdermal administration of a compound orsalt of this invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium channels. In one embodiment, thecompounds are inhibitors of Na_(v)1.8 and thus, without wishing to bebound by any particular theory, the compounds, salts, and compositionsare particularly useful for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity ofNa_(v)1.8 is implicated in the disease, condition, or disorder. Whenactivation or hyperactivity of Na_(v)1.8 is implicated in a particulardisease, condition, or disorder, the disease, condition, or disorder mayalso be referred to as a “Na_(v)1.8 -mediated disease, condition ordisorder.” Accordingly, in another aspect, the invention provides amethod for treating or lessening the severity of a disease, condition,or disorder where activation or hyperactivity of Na_(v)1.8 is implicatedin the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNa_(v)1.8 may be assayed according to methods described generally inInternational Publication No. WO 2014/120808 A9 and U.S. Publication No.2014/0213616 A1, both of which are incorporated by reference in theirentirety, methods described herein, and other methods known andavailable to one of ordinary skill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds, salts, andpharmaceutically acceptable compositions of the invention can beemployed in combination therapies, that is, the compounds, salts, andpharmaceutically acceptable compositions can be administeredconcurrently with, prior to, or subsequent to, one or more other desiredtherapeutics or medical procedures. The particular combination oftherapies (therapeutics or procedures) to employ in a combinationregimen will take into account compatibility of the desired therapeuticsand/or procedures and the desired therapeutic effect to be achieved. Itwill also be appreciated that the therapies employed may achieve adesired effect for the same disorder (for example, an inventive compoundmay be administered concurrently with another agent used to treat thesame disorder), or they may achieve different effects (e.g., control ofany adverse effects). As used herein, additional therapeutic agents thatare normally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.” For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such asNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blockade), neurosurgical (neurolysis ofCNS pathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, NineteenthEdition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp &DohmeCorp., a subsidiary of Merck & Co., Inc., 2011, and the Food and DrugAdministration website, www.fda.gov, the entire contents of which arehereby incorporated by reference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

-   (1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,    oxymorphone, levorphanol, levallorphan, methadone, meperidine,    fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone,    propoxyphene, nalmefene, nalorphine, naloxone, naltrexone,    buprenorphine, butorphanol, nalbuphine, pentazocine, or    difelikefalin;-   (2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,    diclofenac, diflunisal, etodolac, fenbufen, fenoprofen, flufenisal,    flurbiprofen, ibuprofen (including without limitation intravenous    ibuprofen (e.g., Caldolor®)), indomethacin, ketoprofen, ketorolac    (including without limitation ketorolac tromethamine (e.g.,    Toradol®)), meclofenamic acid, mefenamic acid, meloxicam, IV    meloxicam (e.g., Anjeso®), nabumetone, naproxen, nimesulide,    nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam,    sulfasalazine, sulindac, tolmetin or zomepirac;-   (3) a barbiturate sedative, e.g. amobarbital, aprobarbital,    butabarbital, butalbital, mephobarbital, metharbital, methohexital,    pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal or    thiopental;-   (4) a benzodiazepine having a sedative action, e.g.    chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,    oxazepam, temazepam or triazolam;-   (5) a histamine (H₁) antagonist having a sedative action, e.g.    diphenhydramine, pyrilamine, promethazine, chlorpheniramine or    chlorcyclizine;-   (6) a sedative such as glutethimide, meprobamate, methaqualone or    dichloralphenazone;-   (7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,    chlorzoxazone, cyclobenzaprine, methocarbamol or orphenadrine;-   (8) an NMDA receptor antagonist, e.g. dextromethorphan    ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan    ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,    pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-    piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®), a    combination formulation of morphine and dextromethorphan),    topiramate, neramexane or perzinfotel including an NR2B antagonist,    e.g. ifenprodil, traxoprodil or    (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-    piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(IH)-quinolinone;-   (9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,    guanfacine, dexmedetomidine, modafinil, or    4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-l,    2,3,4-tetrahydroisoquinolin-2-yl)-5-(2-pyridyl) quinazoline;-   (10) a tricyclic antidepressant, e.g. desipramine, imipramine,    amitriptyline or nortriptyline;-   (11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine,    topiramate, lacosamide (Vimpat®) or valproate;-   (12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or    NK-1 antagonist, e.g.    (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11    -tetrahydro-9-methyl-5-(4-    methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione    (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl    Jethoxy-3-(4-fluorophenyl)-4-morpholinyl|-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one    (MK-869), aprepitant, lanepitant, dapitant or    3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine    (2S,3S);-   (13) a muscarinic antagonist, e.g oxybutynin, tolterodine,    propiverine, tropsium chloride, darifenacin, solifenacin, temiverine    and ipratropium;-   (14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,    parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;-   (15) a coal-tar analgesic, in particular paracetamol;-   (16) a neuroleptic such as droperidol, chlorpromazine, haloperidol,    perphenazine, thioridazine, mesoridazine, trifluoperazine,    fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,    quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin,    iloperidone, perospirone, raclopride, zotepine, bifeprunox,    asenapine, lurasidone, amisulpride, balaperidone, palindore,    eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or    sarizotan;-   (17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide)    or antagonist (e.g. capsazepine, GRC-15300);-   (18) a beta-adrenergic such as propranolol;-   (19) a local anesthetic such as mexiletine;-   (20) a corticosteroid such as dexamethasone;-   (21) a 5-HT receptor agonist or antagonist, particularly a    5-HT_(1B/1D) agonist such as eletriptan, sumatriptan, naratriptan,    zolmitriptan or rizatriptan;-   (22) a 5-HT_(2A) receptor antagonist such as    R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol    (MDL-100907);-   (23) a cholinergic (nicotinic) analgesic, such as ispronicline    (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-l-amine (RJR-2403),    (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;-   (24) Tramadol®, Tramadol ER (Ultram ER®), IV Tramadol, Tapentadol ER    (Nucynta®);-   (25) a PDE5 inhibitor, such as    5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one    (sildenafil),    (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’:6,1]-pyrido[3,4-b]indole-1,4-dione    (IC-351 or tadalafil),    2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one    (vardenafil),    5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-    pyrazolo[4,3-d]pyrimidin-7-one,    5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,    5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-    pyrazolo[4,3-d]pyrimidin-7-one,    4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,    3-(1-    methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;-   (26) an alpha-2-delta ligand such as gabapentin (Neurontin®),    gabapentin GR (Gralise®), gabapentin, enacarbil (Horizant®),    pregabalin (Lyrica®), 3-methyl gabapentin,    (1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic    acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,    (3S,5R)-3-amino-5-methyl-heptanoic acid,    (3S,5R)-3-amino-5-methyl-octanoic acid,    (2S,4S)-4-(3-chlorophenoxy)proline,    (2S,4S)-4-(3-fluorobenzyl)-proline,    [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,    3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,    C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,    (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,    (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,    (3S,5R)-3-amino-5-methyl-nonanoic acid,    (3S,5R)-3-amino-5-methyl-octanoic acid,    (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and    (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;-   (27) a cannabinoid such as KHK-6188;-   (28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;-   (29) a serotonin reuptake inhibitor such as sertraline, sertraline    metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine    desmethyl metabolite), fluvoxamine, paroxetine, citalopram,    citalopram metabolite desmethylcitalopram, escitalopram,    d,1-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine,    dapoxetine, nefazodone, cericlamine and trazodone;-   (30) a noradrenaline (norepinephrine) reuptake inhibitor, such as    maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,    tomoxetine, mianserin, bupropion, bupropion metabolite    hydroxybupropion, nomifensine and viloxazine (Vivalan®), especially    a selective noradrenaline reuptake inhibitor such as reboxetine, in    particular (S,S)-reboxetine;-   (31) a dual serotonin-noradrenaline reuptake inhibitor, such as    venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,    clomipramine, clomipramine metabolite desmethylclomipramine,    duloxetine (Cymbalta®), milnacipran and imipramine;-   (32) an inducible nitric oxide synthase (iNOS) inhibitor such as    S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,    S-[2-[(l-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,    S-[2-[(l-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,    (2S,SZ)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,    2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;    2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-    thiazolyl)butyl]thio]-4-chlorobenzonitrile,    (2S,4R)-2-amino-4-[[2-chloro-5-    (trifluoromethyl)phenyl]thio]-5-thiazolebutanol,    2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)    butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,    2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,    N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,    NXN-462, or guanidinoethyldisulfide;-   (33) an acetylcholinesterase inhibitor such as donepezil;-   (34) a prostaglandin E2 subtype 4 (EP4) antagonist such as    N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-    methylbenzenesulfonamide or    4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-    yl]carbonyl}amino)ethyl]benzoic acid;-   (35) a leukotriene B4 antagonist; such as    1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic    acid (CP- 105696),    5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric    acid (ONO-4057) or DPC-11870;-   (36) a 5-lipoxygenase inhibitor, such as zileuton,    6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone    (ZD-2138), or 2,3,5- trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone    (CV-6504);-   (37) a sodium channel blocker, such as lidocaine, lidocaine plus    tetracaine cream (ZRS-201) or eslicarbazepine acetate;-   (38) a Na_(v)1.7 blocker, such as XEN-402, XEN403, TV-45070,    PF-05089771, CNV1014802, GDC-0276, RG7893, BIIB-074 (Vixotrigine),    BIIB-095, ASP-1807, DSP-3905, OLP-1002, RQ-00432979, FX-301,    DWP-17061, IMB-110, IMB-111, IMB-112 and such as those disclosed in    WO2011/140425 (US2011/306607); WO2012/106499 (US2012196869);    WO2012/112743 (US2012245136); WO2012/125613 (US2012264749),    WO2012/116440 (US2014187533), WO2011026240 (US2012220605),    US8883840, US8466188, or WO2013/109521 (US2015005304), the entire    contents of each application hereby incorporated by reference.-   (38a) a Na_(v)1.7 blocker such as    (2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl)-(4-isopropoxy-3-methyl-phenyl)methanone,    2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,    [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone,    1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol,    (4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,    [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone,    (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,    5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carbonyl]phenyl]pyridine-2-carbonitrile,    (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,    2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,    2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,    2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,    (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,    2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,    1-[(3S)-2,3-dimethyl-1′-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2,2-trifluoro-ethanone,    [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone,    2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,    1-[1′-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2-dimethyl-propan-1-one,    (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,    [2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone,    4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamide    or    (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone.-   (39) a Na_(v)1.8 blocker, such as PF-04531083, PF-06372865 and such    as those disclosed in WO2008/135826 (US2009048306), WO2006/011050    (US2008312235), WO2013/061205 (US2014296313), US20130303535,    WO2013131018, US8466188, WO2013114250 (US2013274243), WO2014/120808    (US2014213616), WO2014/120815 (US2014228371) WO2014/120820    (US2014221435), WO2015/010065 (US20160152561), WO2015/089361    (US20150166589), WO2019014352 (US20190016671), WO2018/213426,    WO2020/146682, WO2020/146612, WO2020/014243, WO2020/014246,    WO2020/092187, and WO2020/092667 (US2020140411), the entire contents    of each application hereby incorporated by reference.-   (39a) a Na_(v)1.8 blocker such as    4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,    2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,    4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,    4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,    2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,    N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide,    2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,    5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,    N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,    2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,    2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,    5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,    4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,    5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,    2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,    N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide,    2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,    N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,    2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,    2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide,    [4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl[amino]-2-oxo-1-pyridyl]methyl    dihydrogen phosphate,    2-(4-fluoro-2-(methyl-d₃)phenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,    (4-(2-(4-fluoro-2-(methyl-d₃)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl    dihydrogen phosphate,    3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide,    3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,    3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,    3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,    4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic    acid,    2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide,    2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide,    3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,    N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide,    N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide,    3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,    5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinic    acid,    3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide,    3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide,    3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,    N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,    N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,    4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoic    acid,    N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,    5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic    acid,    5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic    acid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoic    acid,    5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinic    acid,    4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoic    acid,    5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinic    acid,    4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoic    acid,    5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic    acid,    4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoic    acid,    4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoic    acid,    4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoic    acid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoic    acid,    5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic    acid,    5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinic    acid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoic    acid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic    acid,    5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic    acid,    5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic    acid, 4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic    acid, 5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic    acid,    2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,    2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,    2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,    2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,    2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide,    2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide,    2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,    2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,    2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,    5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,    4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide,    2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide,    2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,    2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide,    2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide,    5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide,    2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide,    2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,    4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide,    2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,    5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,    2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide,    N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,    N-(3-carbamoyl-4-fluorophenyl)-2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzamide,    4-[[2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,    4-[[3-chloro-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide,    4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,    N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide,    4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethoxy)benzoyl]amino]pyridine-2-carboxamide,    N-(3-carbamoyl-4-fluoro-phenyl)-6-[2-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-methyl-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2,3,4-trifluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzamide,    N-(2-carbamoyl-4-pyridyl)-3-fluoro-5-[2-methoxy-4-(trifluoromethoxy)phenoxy]-2-(trifluoromethyl)pyridine-4-carboxamide,    4-[[6-[2-(difluoromethoxy)-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,    N-(3-carbamoyl-4-fluoro-phenyl)-6-[3-chloro-4-(trifluoromethoxy)phenoxy]-2-fluoro-3-(trifluoromethyl)benzamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,    N-(4-carbamoyl-3-fluoro-phenyl)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,    4-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[3-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-5-(1,1,2,2,2-pentafluoroethyl)benzamide,    4-[[4-(difluoromethoxy)-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-[2-fluoro-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzamide,    4-[[4-cyclopropyl-2-fluoro-6-[2-methoxy-4-(trifluoromethoxy)phenoxy]benzoyl]amino]pyridine-2-carboxamide,    N-(3-carbamoyl-4-fluoro-phenyl)-5-fluoro-2-[2-methoxy-4-(trifluoromethoxy)phenoxy]-4-(trifluoromethyl)benzamide,    5-[[2-fluoro-6-[2-(trideuteriomethoxy)-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide,    N-(3-carbamoyl-4-fluoro-phenyl)-2-fluoro-6-(4-fluorophenoxy)-3-(trifluoromethyl)benzamide,    or    4-[[2-fluoro-6-[3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy]-3-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxamide;-   (40) a combined Na_(v)1.7 and Na_(v)1.8 blocker, such as DSP-2230,    Lohocla201 or BL-1021;-   (41) a 5-HT3 antagonist, such as ondansetron;-   (42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®,    Qutenza®); and the pharmaceutically acceptable salts and solvates    thereof;-   (43) a nicotinic receptor antagonist, such as varenicline;-   (44) an N-type calcium channel antagonist, such as Z-160;-   (45) a nerve growth factor antagonist, such as tanezumab;-   (46) an endopeptidase stimulant, such as senrebotase;-   (47) an angiotensin II antagonist, such as EMA-401;-   (48) acetaminophen (including without limitation intravenous    acetaminophen (e.g., Ofirmev®));-   (49) bupivacaine (including without limitation bupivacaine liposome    injectable suspension (e.g., Exparel®), bupivacaine ER (Posimir),    bupivacaine collagen (Xaracoll) and transdermal bupivacaine    (Eladur®)); and-   (50) bupivacaine and meloxicam combination (e.g., HTX-011).

In one embodiment, the additional appropriate therapeutic agents areselected from V-116517, Pregabalin, controlled release Pregabalin,Ezogabine (Potiga®). Ketamine/amitriptyline topical cream (Amiket®),AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine(Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 orARC-4558.

In another embodiment, the additional appropriate therapeutic agents areselected fromN-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide;N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide;or3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

In another embodiment, the additional therapeutic agent is selected froma GlyT⅖HT2 inhibitor, such as Operanserin (VVZ149), a TRPV modulatorsuch as CA008, CMX-020, NEO6860, FTABS, CNTX4975, MCP101, MDR16523, orMDR652, a EGR1 inhibitor such as Brivoglide (AYX1), an NGF inhibitorsuch as Tanezumab, Fasinumab, ASP6294, MEDI7352, a Mu opioid agonistsuch as Cebranopadol, NKTR181 (oxycodegol), a CB-1 agonist such asNEO1940 (AZN1940), an imidazoline 12 agonist such as CR4056 or ap75NTR-Fc modulator such as LEVI-04.

In another embodiment, the additional therapeutic agent is oliceridineor ropivacaine (TLC590).

In another embodiment, the additional therapeutic agent is a Na_(v)1.7blocker such as ST-2427 and those disclosed in WO2010129864,WO2015157559, WO2017059385, WO2018183781, WO2018183782, and WO2020072835the entire contents of each application hereby incorporated byreference.

In another embodiment, the additional therapeutic agent is ASP18071,CC-8464, ANP-230, ANP-231, NOC-100, NTX-1175, ASN008, NW3509, AM-6120,AM-8145, AM-0422, BL-017881, NTM-006, Opiranserin (Unafra™),brivoligide, SR419, NRD.E1, LX9211, LY3016859, ISC-17536, NFX-88,LAT-8881, AP-235, NYX 2925, CNTX-6016, S-600918, S-637880, RQ-00434739,KLS-2031, MEDI 7352, or XT-150.

In another embodiment, the additional therapeutic agent is a sodiumchannel inhibitor (also known as a sodium channel blocker), such as theNa_(v)1.7 and Na_(v)1.8 blockers identified above.

The amount of additional therapeutic agent present in the compositionsof this invention may be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. The amount of additional therapeutic agent in thepresently disclosed compositions may range from about 10% to 100% of theamount normally present in a composition comprising that agent as theonly therapeutically active agent.

The compounds and salts of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound or salt of the invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the invention includes an implantable device coated with acomposition comprising a compound or salt of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. Suitable coatings and thegeneral preparation of coated implantable devices are described in U.S.Pats. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccharides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na_(v)1.8 activityin a biological sample or a subject, which method comprisesadministering to the subject, or contacting said biological sample witha compound of the invention, a pharmaceutically acceptable salt thereof,or a pharmaceutical composition thereof. The term “biological sample,”as used herein, includes, without limitation, cell cultures or extractsthereof, biopsied material obtained from a mammal or extracts thereof;and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof.

Inhibition of Na_(v)1.8 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumchannels in biological and pathological phenomena; and the comparativeevaluation of new sodium channel inhibitors.

Synthesis of the Compounds of the Invention

The compounds of the invention can be prepared from known materials bythe methods described in the Examples, other similar methods, and othermethods known to one skilled in the art. As one skilled in the art wouldappreciate, the functional groups of the intermediate compounds may needto be protected by suitable protecting groups. Protecting groups may beadded or removed in accordance with standard techniques, which arewell-known to those skilled in the art. The use of protecting groups isdescribed in detail in T.G.M. Wuts et al., Greene’s Protective Groups inOrganic Synthesis (4th ed. 2006).

Radiolabeled Analogs of the Compounds of the Invention

In another aspect, the invention relates to radiolabeled analogs of thecompounds of the invention. As used herein, the term “radiolabeledanalogs of the compounds of the invention” refers to compounds that areidentical to the compounds of the invention, as described herein(including all embodiments thereof), except that one or more atoms hasbeen replaced with a radioisotope of the atom present in the compoundsof the invention.

As used herein, the term “radioisotope” refers to an isotope of anelement that is known to undergo spontaneous radioactive decay. Examplesof radioisotopes include ³H, ¹⁴C, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and the like, aswell as the isotopes for which a decay mode is identified in V.S.Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division,Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

The radiolabeled analogs can be used in a number of beneficial ways,including in various types of assays, such as substrate tissuedistribution assays. For example, tritium (³H)- and/or carbon-14(¹⁴C)-labeled compounds may be useful for various types of assays, suchas substrate tissue distribution assays, due to relatively simplepreparation and excellent detectability.

In another aspect, the invention relates to pharmaceutically acceptablesalts of the radiolabeled analogs, in accordance with any of theembodiments described herein in connection with the compounds of theinvention.

In another aspect, the invention relates to pharmaceutical compositionscomprising the radiolabeled analogs, or pharmaceutically acceptablesalts thereof, and a pharmaceutically acceptable carrier, adjuvant orvehicle, in accordance with any of the embodiments described herein inconnection with the compounds of the invention.

In another aspect, the invention relates to methods of inhibitingvoltage-gated sodium channels and methods of treating or lessening theseverity of various diseases and disorders, including pain, in a subjectcomprising administering an effective amount of the radiolabeledanalogs, pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions thereof, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

In another aspect, the invention relates to radiolabeled analogs,pharmaceutically acceptable salts thereof, and pharmaceuticalcompositions thereof, for use, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

In another aspect, the invention relates to the use of the radiolabeledanalogs, or pharmaceutically acceptable salts thereof, andpharmaceutical compositions thereof, for the manufacture of medicaments,in accordance with any of the embodiments described herein in connectionwith the compounds of the invention.

In another aspect, the radiolabeled analogs, pharmaceutically acceptablesalts thereof, and pharmaceutical compositions thereof, can be employedin combination therapies, in accordance with any of the embodimentsdescribed herein in connection with the compounds of the invention.

EXAMPLES

General methods. ¹H NMR (400 MHz) spectra were obtained as solutions inan appropriate deuterated solvent such as dimethyl sulfoxide-d₆(DMSO-d₆).

Analytical supercritical fluid chromatography (SFC) separation ofvarious isomeric mixtures was accomplished using a Waters UPC2-SFCinstrument comprising a convergence manager, a sample manager, a binarysolvent manager, a column manager-30S, a PDA detector, an isocraticsolvent manager and a QDa detector. Columns used include those bymanufactured by Regis Technologies (e.g., R′R Whelk 0-1, 3.5 µm particlesize, 5.0 cm x 3.0 mm size) with a mobile phase of Solvent A: liquid CO₂(58-60 bar/40° C.) Solvent B: methanol HPLC grade with 20 mM NH₃ at aflow rate of 2 ml/min and an injection volume of 2 µl. Gradient: at 0min (95:5) A:B, at 3.5 min (50:50) A:B, at 3.55 min (40:60) A:B, at 3.95min (40:60) A:B and at 4.0 min (95:5) A:B. Samples for analytical SFCwere dissolved in methanol at approximately 0.5 mg/ml concentration.

Preparative SFC used the same stationary and mobile phases as thosedescribed above for analytical SFC but the samples were purified using adifferent instrument and gradient method as follows. Preparative SFCseparation of various isomeric mixtures was accomplished using a WatersPrep-100 SFC instrument comprising a Back Pressure Regulator, a 2767Sample Manager, a 2545 Quarternary Gradient Module, a Column Oven, a2998 PDA detector, an Isocratic Solvent Manager, a P-200 CO₂ pump, SFCFlow Splitter-100, 3 Heat exchangers, a Series III LC pump and a QDadetector. Columns used include those manufactured by Regis Technologies(e.g., R′R Whelk 0-1, 5.0 µm particle size, 25.0 cm x 21.1 mm size) witha mobile phase of Solvent A: liquid CO₂ (58-60 bar/40° C.) Solvent B:methanol HPLC grade with 20 mM NH₃ at a flow rate of 100 ml/min and aninjection volume of 500 µl (50 mg crude loading), 2:1 ratio of methanolto dichloroethane was used for solubilization and SFC injection of crudecompound. For injection 500 µl/50 mg loading the following method wasused: Isocratic: at 0 min to 7.6 min (80:20) A:B, Gradient: at 8.1 min(75:25) A:B, Isocratic at 8.2 to 10.6 min (75:25) (A:B), Gradient: at10.7 min (80:20) A:B and Isocratic: at 11 min (80:20) (A:B). Forinjection 1500 µl/150 mg loading the following method was used:Isocratic: at 0 min to 7.5 min (80:20) A:B, Gradient: at 7.6 min (75:25)A:B, Gradient: at 8.1 min (60:40) A:B, Isocratic: at 8.7 min to 10.6 min(60:40) A:B, Gradient: at 10.7 min (80:20) A:B and Isocratic: at 12 min(80:20) A:B.

LC/MS Method: LC/MS analysis was conducted using an Acquity UPLC BEH C₈column (50 × 2.1 mm, 1.7 µm particle) made by Waters (pn: 186002877)with a (2.1 × 5 mm, 1.7 µm particle) guard column (pn: 186003978), and adual gradient run from 2-98% mobile phase B over 4.45 minutes. Mobilephase A = H₂O (10 mM ammonium formate with 0.05 % ammonium hydroxide).Mobile phase B = acetonitrile. Flow rate = 0.6 mL/min, injection volume= 2 µL, and column temperature = 45° C.

X-ray powder diffraction (XRPD) analysis was performed at roomtemperature in transmission mode using a PANalytical Empyrean systemequipped with a sealed tube source and a PIXcel 1D Medipix-3 detector(Malvern PANalytical Inc, Westborough, Massachusetts). The X-Raygenerator operated at a voltage of 45 kV and a current of 40 mA withcopper radiation (1.54060 Å). The powder sample was placed on a 96 wellsample holder with mylar film and loaded into the instrument. The samplewas scanned over the range of about 3° to about 40°20 with a step sizeof 0.0131303° and 49 s per step.

Solid state NMR analysis was conducted on a Bruker-Biospin 400 MHzwide-bore spectrometer equipped with Bruker-Biospin 4 mm HFX probe wasused. Samples were packed into 4 mm ZrO₂ rotors and spun under MagicAngle Spinning (MAS) condition with spinning speed typically set to 12.5kHz. The proton relaxation time was measured using ¹H MAS T₁ saturationrecovery relaxation experiment in order to set up proper recycle delayof the ¹³C cross-polarization (CP) MAS experiment. The fluorinerelaxation time was measured using ¹⁹F MAS T₁ saturation recoveryrelaxation experiment in order to set up proper recycle delay of the ¹⁹FMAS experiment. The CP contact time of carbon CPMAS experiment was setto 2 ms. A CP proton pulse with linear ramp (from 50% to 100%) wasemployed. The carbon Hartmann-Hahn match was optimized on externalreference sample (glycine). Both carbon and fluorine spectra wererecorded with proton decoupling using TPPM15 decoupling sequence withthe field strength of approximately 100 kHz.

Thermogravimetric analysis (TGA) data were collected on a TA DiscoveryThermogravimetric Analyzer or equivalent instrumentation. A sample withweight of approximately 1-5 mg was scanned from 25° C. to 350° C. at aheating rate of 10° C./min. Data were collected by Thermal Advantage QSeriesTM software and analyzed by Trios and/or Universal Analysissoftware (TA Instruments, New Castle, DE).

Differential scanning calorimetry (DSC) data were acquired using a TAInstruments Q2000 or equivalent instrumentation. A sample with a weightbetween 1 and 10 mg was weighed into an aluminum pan. This pan wasplaced in the sample position in the calorimeter cell. An empty pan wasplaced in the reference position. The calorimeter cell was closed and aflow of nitrogen was passed through the cell. The heating program wasset to heat the sample at a heating rate of 10° C./min to a temperatureof 300° C. When the run was completed, the data were analyzed by Triosand/or Universal Analysis software (TA Instruments, New Castle, DE).

Infrared (IR) spectra were collected using a Thermo Scientific NicoletiS50 Spectrometer equipped with a diamond ATR sampling accessory.

X-ray diffraction data were acquired on a Bruker diffractometer equippedwith Cu K_(α) radiation (λ=1.5478 Å) and a CCD detector. The structurewas solved and refined using SHELX programs (Sheldrick, G.M., ActaCryst., (2008) A64, 112-122).

Abbreviations

Unless otherwise noted, or where the context dictates otherwise, thefollowing abbreviations shall be understood to have the followingmeanings:

Abbreviation Meaning NMR Nuclear magnetic resonance ESI-MS Electrospraymass spectrometry LC/MS Liquid chromatography-mass spectrometry UPLCUltra performance liquid chromatography HPLC/MS/MS High performanceliquid chromatography/tandem mass spectrometry IS Internal standard HPLCHigh performance liquid chromatography SFC Supercritical fluidchromatography MDAP Mass directed auto purification ESI Electrosprayionization LED Light-emitting diode g grams mg milligrams L Liter(s) mLMilliliters µL Microliters nL nanoliters mmol millimoles hr, h hours minMinutes ms millisecond mm Millimeters µm Micrometers nm nanometer MHzMegahertz Hz Hertz N Normal (concentration) M Molar (concentration) mMMillimolar (concentration) µM Micromolar (concentration) ppm Parts permillion % w/v Weight-volume concentration ArBPin2-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanet-BuOH tert-butyl alcohol DAST Diethylaminosulfur trifluoride DCMDichloromethane DCE Dichloroethane DIEA, DIPEA N, N-Diisopropyl ethylamine DMA N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide DRG Dorsal root ganglia EtOH Ethanol EtOAc Ethyl acetate HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate EDCI1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide T3P Propylphosphonicanhydride, i.e., 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide TCFH N,N,N′,N′-Tetramethylchloroformamidiniumhexafluorophosphate MeOH Methanol MTBE Methyl tert-butyl ether NMPN-Methylpyrrolidone THF Tetrahydrofuran TEA triethylamine RB Roundbottom (flask) RT Room temperature ca. Circa (approximately) E-VIPRElectrical stimulation voltage ion probe reader HEK Human embryonickidney KIR2.1 Inward-rectifier potassium ion channel 2.1 DMEM Dulbecco’sModified Eagle’s Medium FBS Fetal bovine serum NEAA Non-essential aminoacids HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acidDiSBAC₆(3) Bis-(1,3-dihexyl-thiobarbituric acid) trimethine oxonolCC2-DMPE Chlorocoumarin-2-dimyristoyl phosphatidylethanolamine VABSC-1Voltage Assay Background Suppression Compound HS Human serum BSA BovineSerum Albumin

Example 1Rel-(2S,3R,4R,5S)-4-[[3-[2-(Difluoromethoxy)-4-Fluoro-Phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]amino]Pyridine-2-Carboxamide(1) andRel-(2R,3S,4S,5R)-4-[[3-[2-(Difluoromethoxy)-4-Fluoro-phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]amino]Pyridine-2-Carboxamide(2)

Step 1

A mixture of ethylrac-(2S,3R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(3.0 g, 7.77 mmol),2-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(“ArBPin”, 2.33 g, 8.09 mmol), Pd(PPh₃)₄ (380 mg, 0.33 mmol), and sodiumcarbonate (16 mL of 2 M, 32.00 mmol) in dioxane (60 mL) was heated at100° C. for 1 hour. The solution was diluted in EtOAc and water, thelayers separated and the organic layer washed with brine, dried (MgSO₄),filtered and concentrated in vacuo. Purification by flash chromatography(220 g SiO₂, 0 to 30% EtOAc in petroleum ether) gave ethylrac-(2S,3R)-4-[2-(difluoromethoxy)-4-fluoro-phenyl]-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(2.0 g, 65%). ¹H NMR (500 MHz, Chloroform-d) δ 7.19 (dd, J = 8.5, 6.4Hz, 1H), 6.99 - 6.89 (m, 2H), 6.44 (t, J = 73.3 Hz, 1H), 4.14 (qd, J =7.1, 1.7 Hz, 2H), 3.45 (q, J = 7.4 Hz, 1H), 1.72 - 1.65 (m, 3H), 1.14(t, J = 7.1 Hz, 3H), 1.12 - 1.08 (m, 3H) ppm. ESI-MS m/z calc.398.09528, found 399.0 (M+1)⁺.

Step 2

Magnesium filings (3.5 g, 144.0 mmol) were ground in a mortar and addedto a solution of ethylrac-(2S,3R)-4-[2-(difluoromethoxy)-4-fluoro-phenyl]-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(2.0 g, 5.02 mmol) in MeOH (60 mL). The flask was purged with nitrogenand the reaction was stirred at ambient temperature until the observedexotherm finished (30 mins). The reaction was then heated at 90° C. for3 hours before being cooled to 0° C. and quenched and acidified bycareful addition of 2 M HCl. The mixture was concentrated in vacuo andextracted with DCM (3 × 100 mL). The combined organic layers were dried(MgSO₄), filtered and concentrated in vacuo to give methylrac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.7 g, 88%) as a mixture of epimers at the position adjacent to theester (stereochemical assignments tentative). ESI-MS m/z calc.386.09528, found 387.0 (M+1)⁺.

Step 3

To a solution of methylrac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(3.2 g, 8.28 mmol) in t-BuOH (80 mL) was added KOt-Bu (4.25 g, 37.87mmol). The reaction was stirred at ambient temperature overnight thenquenched by addition of saturated aqueous NH₄Cl solution and dilutedwith EtOAc. The aqueous layer was separated and extracted with EtOAc andthe combined organic layers were dried (MgSO₄), filtered andconcentrated in vacuo. The residue was dissolved in EtOH (20 mL) andLiOH (15 mL of 2 M, 30.00 mmol) and the mixture stirred at 110° C. for 1hour. The reaction was quenched by addition of saturated aqueous NH₄Clsolution and diluted with EtOAc. The aqueous layer was separated andextracted with EtOAc and the combined organic layers were dried overMgSO₄, filtered, and concentrated in vacuo. Purification by flashchromatography (80 g SiO₂, 0 to 100% EtOAc in heptanes) gaverac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (2.2 g, 71%) as a mixture of epimers at the position adjacent tothe ester (stereochemical assignments tentative). ESI-MS m/z calc.372.07962, found 371.2 (M-1)⁻.

Step 4

To a solution ofrac-(3R,4R,5S)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (650 mg, 1.75 mmol) in DCM (24 mL) stirring at 0° C. was added DMF(50 µL, 0.65 mmol) and oxalyl chloride (400 µL, 4.59 mmol). The reactionwas warmed to ambient temperature over 30 mins then concentrated invacuo. The residue was further dried on a high-vacuum apparatus for 5mins to give a white foam, which was dissolved in DCM (24 mL) and addeddropwise to a solution of methyl 4-aminopyridine-2-carboxylate (305 mg,2.01 mmol) and NEt₃ (800 µL, 5.74 mmol) in DCM (9 mL) with stirring at0° C. The reaction was warmed to ambient temperature over 4 hours, thenquenched by addition of MeOH (2 mL) and concentrated in vacuo.Purification by flash chromatography (12 g SiO₂, 0 to 70% EtOAc inheptane, loaded in DCM) gave methylrac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(840 mg, 95%), as a 85:15 mixture of epimers at the position adjacent tothe amide (stereochemical assignments tentative). ESI-MS m/z calc.506.12766, found 507.9 (M+1)⁺.

Step 5

A solution of methylrac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(740 mg, 1.46 mmol) in methanolic ammonia (15 mL of 7 M, 105.0 mmol) wasstirred in a sealed vessel at 100° C. for 16 hours. The solution wasconcentrated in vacuo to giverac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(700 mg, 98%) as a mixture of epimers at the position adjacent to theamide (stereochemical assignments tentative). ESI-MS m/z calc.491.12796, found 491.7 (M+1)⁺.

Step 6

Purification ofrac-(3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(400 mg, 0.81 mmol) by chiral SFC using a Chiralpak IC column, 5umparticle size, 25 cm x 20 mm from Daicel gave:

First Eluting Isomer (rt = 3.40 min):rel-(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(1, 150 mg, 74%) (stereochemical assignments tentative). ¹H NMR (500MHz, Methanol-d₄) δ 8.48 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H),7.90 (dd, J = 5.5, 2.2 Hz, 1H), 7.49 (dd, J = 9.0, 6.3 Hz, 1H), 7.01(dd, J = 9.0, 6.7 Hz, 2H), 7.14 - 6.74 (m, 1H), 5.14 (d, J = 10.3 Hz,1H), 4.33 (dd, J = 10.3, 7.9 Hz, 1H), 2.83 (p, J = 7.6 Hz, 1H), 1.66 (s,3H), 0.83 (dd, J = 7.7, 2.3 Hz, 3H) ppm. ESI-MS m/z calc. 491.12796,found 492.2 (M+1)⁺; 490.3 (M-1)⁻.

Second Eluting Isomer (rt = 4.28 min): The second eluting isomer waspurified further by reverse phase preparative HPLC (basic eluent) togiverel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(2, 100 mg, 50%) (stereochemical assignments tentative). ¹H NMR (500MHz, Methanol-d₄) δ 8.49 (d, J = 5.5 Hz, 1H), 8.27 - 8.23 (m, 1H), 7.90(dd, J = 5.5, 2.2 Hz, 1H), 7.49 (dd, J = 9.1, 6.4 Hz, 1H), 7.06 - 6.99(m, 2H), 7.16 - 6.69 (m, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.33 (dd, J =10.3, 7.9 Hz, 1H), 2.83 (p, J = 7.6 Hz, 1H), 1.66 (d, J = 1.3 Hz, 3H),0.83 (dd, J = 7.6, 2.3 Hz, 3H) ppm. ESI-MS m/z calc. 491.12796, found492.1 (M+1)⁺.

The following compound was made using a similar method to that describedin Example 1, but no SFC separation step 6 was carried out at the end ofthe synthesis, and the compound was isolated as a racemate:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 28rac-(2S,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 491.12796,found 492.0 (M+1)⁺; Retention time: 3.12 minutes ¹H NMR (500 MHz,Chloroform-d) δ 8.46 (d, J = 5.5 Hz, 1H), 8.05 (dd, J = 5.6, 2.2 Hz,1H), 7.96 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.44 (dd, J = 8.7, 6.1 Hz,1H), 6.99 (td, J = 8.3, 2.6 Hz, 1H), 6.90 (dd, J = 9.5, 2.5 Hz, 1H),6.54 (t, J = 72.8 Hz, 1H), 5.61 (s, 1H), 5.00 (d, J = 9.3 Hz, 1H), 4.26(t, J = 8.7 Hz, 1H), 3.08 - 2.93 (m, 1H), 1.43 (s, 3H), 0.74 (d, J = 7.4Hz, 3H) ppm.

The following compounds were made using a similar method to thatdescribed in Example 1, but using methylamine at 40° C. in step 5. Theconditions used for the epimerization/hydrolysis step 3 followed theconditions described in Example 11 step 5. The purification in step 6was conducted by chiral SFC using a Chiralpak AS-H column, 5 µm particlesize, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from BergerInstruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 29rel-(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methylpyridine-2-carboxamide(first eluting peak by SFC on Chiralpak AS-H column, rt = 2.00 min)ESI-MS m/z calc. 505.14362, found 506.5 (M+1)⁺; 504.5 (M-1)⁻; Retentiontime: 3.28 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.43(d, J = 5.5 Hz, 1H), 8.12 (dd, J = 5.5, 2.2 Hz, 1H), 8.07 - 7.98 (m,1H), 7.88 (d, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.8, 6.2 Hz, 1H), 7.00 (td,J = 8.3, 2.6 Hz, 1H), 6.87 (dd, J = 9.3, 2.5 Hz, 1H), 6.53 (d, J = 74.0Hz, 1H), 5.05 (d, J = 11.0 Hz, 1H), 4.09 (dd, J = 11.1, 8.0 Hz, 1H),3.04 (d, J = 5.1 Hz, 3H), 2.80 (p, J = 7.6 Hz, 1H), 1.70 (s, 3H), 0.86-0.75 (m, 3H) ppm. 30rel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methylpyridine-2-carboxamide (second eluting peakby SFC on Chiralpak AS-H column, rt = 3.23 min) ESI-MS m/z calc.505.14362, found 506.5 (M+1)⁺; 504.5 (M-1)⁻; Retention time: 3.28minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.43 (d, J = 5.6Hz, 1H), 8.13 (dd, J = 5.6, 2.2 Hz, 1H), 8.04 (s, 1H), 7.88 (d, J = 2.3Hz, 1H), 7.48 (dd, J = 8.8, 6.2 Hz, 1H), 7.00 (td, J = 8.3, 2.5 Hz, 1H),6.87 (dd, J = 9.2, 2.5 Hz, 1H), 6.53 (d, J = 72.7 Hz, 1H), 5.05 (d, J =11.1 Hz, 1H), 4.09 (dd, J = 11.1, 8.0 Hz, 1H), 3.04 (d, J = 5.0 Hz, 3H),2.80 (p, J = 7.6 Hz, 1H), 1.72 - 1.68 (m, 3H), 0.86 - 0.75 (m, 3H) ppm.

The following compounds were made using a similar method to thatdescribed in Example 1, except that 5-amino-2-fluorobenzamide was usedas coupling partner in step 4, and step 5 was omitted. The conditionsused for the epimerization/hydrolysis step 3 followed the conditionsdescribed in Example 11 step 5. The purification in step 6 was conductedby chiral SFC using a Chiralpak AS-H column, 5 um particle size, 25 cm x10 mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 31rel-(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (first eluting peak by SFC on Chiralpak AS-H column, rt= 1.79 min) ESI-MS m/z calc. 508.1233, found 507.1 (M-1)⁻; Retentiontime: 3.22 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.13(ddd, J = 9.0, 4.5, 2.9 Hz, 1H), 7.90 (dd, J = 6.6, 2.9 Hz, 1H), 7.49(dd, J = 8.8, 6.1 Hz, 1H), 7.10 (dd, J = 11.3, 9.0 Hz, 1H), 6.98 (td, J= 8.3, 2.6 Hz, 1H), 6.86 (dd, J = 9.3, 2.6 Hz, 1H), 6.70 (d, J = 12.2Hz, 1H), 6.68 - 6.35 (m, 1H), 5.88 (s, 1H), 5.05 (d, J = 11.0 Hz, 1H),4.09 (dd, J = 11.0, 7.9 Hz, 1H), 2.79 (p, J = 7.6 Hz, 1H), 1.69 (d, J =1.1 Hz, 3H), 0.84 -0.75 (m, 3H) ppm. 32rel-(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (second eluting peak by SFC on Chiralpak AS-H column, rt= 3.07 min) ESI-MS m/z calc. 508.1233, found 507.1 (M-1)⁻; Retentiontime: 3.22 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.13(ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 7.90 (dd, J = 6.6, 2.9 Hz, 1H), 7.49(dd, J = 8.8, 6.2 Hz, 1H), 7.10 (dd, J = 11.2, 9.0 Hz, 1H), 6.98 (ddd, J= 8.8, 7.9, 2.6 Hz, 1H), 6.86 (dd, J = 9.2, 2.5 Hz, 1H), 6.70 (d, J =12.0 Hz, 1H), 6.68 - 6.32 (m, 1H), 5.86 (s, 1H), 5.05 (d, J = 11.0 Hz,1H), 4.09 (dd, J = 11.0, 7.9 Hz, 1H), 2.79 (p, J = 7.6 Hz, 1H), 1.69 (d,J=1.1 Hz, 3H), 0.83 -0.76 (m, 3H) ppm.

The following compounds were made using a similar method to thatdescribed in Example 1, but using catalytic 1,2-dibromoethane toactivate the magnesium in step 2 and without the separation of theracemate by chiral SFC in step 6:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 33rac-(2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 473.1374,found 474.0 (M+1)⁺; Retention time: 3.19 minutes ¹H NMR (500 MHz,Chloroform-d) δ 8.55 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.07 (dd, J =5.5, 2.1 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.10 - 7.01(m, 1H), 6.90 (q, J = 8.7 Hz, 1H), 5.51 (s, 1H), 4.96 (d, J = 9.0 Hz,1H), 4.24 (t, J = 8.5 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 2.97 (q, J =7.5 Hz, 1H), 1.42 (s, 3H), 0.72 (d, J = 7.4 Hz, 3H) ppm. 34rac-(2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 473.1374,found 474.1 (M+1)⁺; Retention time: 3.15 minutes ¹H NMR (500 MHz,Chloroform-d) δ 8.55 (s, 1H), 8.46 (d, J = 5.5 Hz, 1H), 8.08 (dd, J =5.5, 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H), 7.01 - 6.86(m, 2H), 5.55 (s, 1H), 4.74 (d, J = 9.7 Hz, 1H), 3.99 (d, J = 2.3 Hz,3H), 3.68 (t, J = 11.0 Hz, 1H), 2.52 (dd, J = 12.1, 6.9 Hz, 1H), 1.63-1.58 (m, 3H), 1.03 (dd, J = 7.2, 2.1 Hz, 3H) ppm. 35rac-(2R,3S,4R,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 473.1374,found 474.0 (M+1)⁺; Retention time: 3.22 minutes ¹H NMR (500 MHz,Methanol-d₄) δ 8.48 (dd, J = 5.5, 0.6 Hz, 1H), 8.24 (dd, J = 2.2, 0.6Hz, 1H), 7.86 (dd, J = 5.5, 2.2 Hz, 1H), 7.12 (ddd, J = 8.2, 5.6, 2.2Hz, 1H), 7.02 (ddd, J = 9.8, 8.9, 7.5 Hz, 1H), 4.63 (d, J = 10.4 Hz,1H), 3.91 (d, J = 2.2 Hz, 3H), 3.62 (dd, J = 12.0, 10.4 Hz, 1H), 3.35(s, 1H), 2.91 (dq, J = 11.9, 6.9 Hz, 1H), 1.51 (d, J = 1.1 Hz, 3H), 0.99(d, J = 6.9 Hz, 3H) ppm.

The following compounds were made using a method similar to thatdescribed in Example 1, but using catalytic 1,2-dibromoethane toactivate the magnesium in step 2, and without the addition of LiOH/EtOHin step 3. The purification in step 6 was conducted by SFC using a DEAPcolumn, 5 µm particle size, 25 cm x 21.2 mm from PrincetonChromatography Inc. on an SFC 100 instrument from Waters Corp., followedby chiral SFC using a Chiralpak AS-H column, 5 µm particle size, 25 cm x10 mm from Daicel on a Minigram SFC instrument from Berger Instruments.Compound 3a was purified further by chiral SFC using a Chiralpak OD-Hcolumn, 5 µm particle size, 25 cm x 10 mm from Daicel on a Minigram SFCinstrument from Berger Instruments. Compounds 38 and 39 were separatedby chiral SFC using a (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x21.2 mm from Regis Technologies:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 3a rel-(2R,3S,4S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (first eluting isomer by SFCon Chiralpak AS-H column, rt = 1.77 min) ESI-MS m/z calc. 455.14682,found 456.6 (M+1)⁺ ; 454.7 (M-1) ⁻; Retention time: 3.16 minutes ¹H NMR(500 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.18(dd, J = 5.6, 2.2 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.85 (s, 1H), 7.35(dd, J = 8.6, 6.4 Hz, 1H), 6.71 (td, J = 8.4, 2.5 Hz, 1H), 6.61 (dd, J =10.7, 2.5 Hz, 1H), 5.62 (s, 1H), 5.08 (d, J = 11.3 Hz, 1H), 4.10 (dd, J= 11.2, 7.7 Hz, 1H), 3.81 (s, 3H), 2.81 (p, J = 7.5 Hz, 1H), 1.70 (d, J= 1.2 Hz, 3H), 0.75 (dq, J = 7.4, 2.4 Hz, 3H) ppm. 3b rel-(2S,3R,4R,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (second eluting isomer by SFCon Chiralpak AS-H column, rt = 2.79 min) ESI-MS m/z calc. 455.14682,found 456.6 (M+1)⁺; 454.7 (M-1)⁻; Retention time: 3.16 minutes 36rel-(2R,3S,4R,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (first eluting isomer by SFCon Chiralpak AS-H column, rt = 2.94 min) ESI-MS m/z calc. 455.14682,found 456.6 (M+1)⁺; 454.6 (M-1)⁻; Retention time: 3.06 minutes ¹H NMR(500 MHz, Methanol-d₄) δ 8.49 (d, J = 5.5 Hz, 1H), 8.18 (d, J = 2.1 Hz,1H), 7.84 (dd, J = 5.5, 2.2 Hz, 1H), 7.30 (dd, J = 8.5, 6.6 Hz, 1H),6.79 (dd, J = 11.0, 2.5 Hz, 1H), 6.71 (td, J = 8.3, 2.5 Hz, 1H), 4.80(s, 1H), 3.78 (s, 3H), 3.77 - 3.71 (m, 1H), 2.84 - 2.70 (m, 1H), 1.60(d, J = 1.1 Hz, 3H), 1.05 - 0.97 (m, 3H) ppm. 37rel-(2S,3R,4S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (second eluting isomer by SFCon Chiralpak AS-H column, rt = 3.66 min) ESI-MS m/z calc. 455.14682,found 456.6 (M+1)⁺; 454.6 (M-1)⁻; Retention time: 3.06 minutes ¹H NMR(500 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.09(dd, J = 5.5, 2.2 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 4.3Hz, 1H), 7.13 (dd, J = 8.3, 6.5 Hz, 1H), 6.71 -6.63 (m, 2H), 5.58 (s,1H), 4.92 (d, J = 9.6 Hz, 1H), 3.82 (s, 3H), 3.54 (t, J = 10.9 Hz, 1H),2.80 -2.67 (m, 1H), 1.62 - 1.58 (m, 3H), 1.01 (dt, J = 7.0, 1.9 Hz, 3H)ppm. 38rel-(2S,3R,4S,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (first eluting isomer by SFCon Whelk01 column, rt = 3.29 min) ESI-MS m/z calc. 455.14682, found456.6 (M+1)⁺; 454.7 (M-1)⁻; Retention time: 3.13 minutes ¹H NMR (500MHz, Chloroform-d) δ 8.58 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.17 (dd, J= 5.5, 2.2 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.86 (s, 1H), 7.14 (dd, J= 8.4, 6.4 Hz, 1H), 6.72 - 6.62 (m, 2H), 5.64 (s, 1H), 4.80 (d, J = 10.6Hz, 1H), 3.78 (s, 3H), 3.30 (t, J = 11.2 Hz, 1H), 3.06 (dq, J = 13.4,6.8 Hz, 1H), 1.51 (s, 3H), 0.96 (d, J = 6.8 Hz, 3H) ppm. 39rel-(2R,3S,4R,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (second eluting isomer by SFCon Whelk01 column, rt = 4.09 min) ESI-MS m/z calc. 455.14682, found456.6 (M+1)⁺; 454.6 (M-1)⁻; Retention time: 3.13 minutes ¹H NMR (500MHz, Chloroform-d) δ 8.59 (s, 1H), 8.47 (d, J = 5.5 Hz, 1H), 8.18 (dd, J= 5.5, 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.87 (s, 1H), 7.16 (dd, J= 8.4, 6.5 Hz, 1H), 6.75 - 6.64 (m, 2H), 5.66 - 5.61 (m, 1H), 4.83 (d, J= 10.6 Hz, 1H), 3.81 (s, 3H), 3.32 (t, J= 11.2 Hz, 1H), 3.09 (dq, J=11.8, 6.9 Hz, 1H), 1.53 (s, 3H), 0.99 (d, J = 6.8 Hz, 3H) ppm. 40rel-(2R,3S,4S,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (first eluting isomer by SFCon Chiralpak AS-H column, rt = 1.87 min) ESI-MS m/z calc. 455.14682,found 456.6 (M+1)⁺; 454.6 (M-1)⁻; Retention time: 3.09 minutes ¹H NMR(500 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.09(dd, J = 5.4, 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.83 (s, 1H),7.34 - 7.27 (m, 1H), 6.70 (td, J = 8.3, 2.5 Hz, 1H), 6.62 (dd, J = 10.8,2.5 Hz, 1H), 5.60 - 5.56 (m, 1H), 5.01 (d, J = 9.1 Hz, 1H), 4.26 (t, J =8.6 Hz, 1H), 3.82 (s, 3H), 3.01 (p, J = 7.5 Hz, 1H), 1.41 (s, 3H), 0.68(d, J = 7.4 Hz, 3H) ppm. 41rel-(2S,3R,4R,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (second eluting isomer by SFCon Chiralpak AS-H column, rt = 2.96 min) ESI-MS m/z calc. 455.14682,found 456.6 (M+1)⁺; 454.7 (M-1)⁻; Retention time: 3.09 minutes ¹H NMR(500 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.45 (d, J = 5.5 Hz, 1H), 8.09(dd, J = 5.6, 2.2 Hz, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.85 - 7.80 (m,1H), 7.30 (dd, J = 8.5, 6.4 Hz, 1H), 6.70 (td, J = 8.3, 2.5 Hz, 1H),6.62 (dd, J = 10.7, 2.5 Hz, 1H), 5.56 (s, 1H), 5.01 (d, J = 9.1 Hz, 1H),4.26 (t, J = 8.6 Hz, 1H), 3.82 (s, 3H), 3.01 (p, J = 7.5 Hz, 1H), 1.41(s, 3H), 0.68 (d, J = 7.4 Hz, 3H) ppm.

The following compounds were made using a method similar to thatdescribed in Example 1, but using catalytic 1,2-dibromoethane toactivate the magnesium in step 2, and without the addition of LiOH/EtOHin step 3. The purification in step 6 was conducted by SFC using a LuxCellulose-2 column, 5 µm particle size, 25 cm x 10 mm from Phenomenex onan SFC 100 instrument from Waters Corp., on a Minigram SFC instrumentfrom Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 42rel-(2R,3S,4S,5R)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (first eluting isomer by SFCon Lux Cellulose-2 column, rt = 4.18 min) ESI-MS m/z calc. 505.14362,found 506.1 (M+1)⁺; 504.1 (M-1)⁻; Retention time: 3.37 minutes ¹H NMR(400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.29 (d, J= 2.1 Hz, 1H), 8.06 (s, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.71 (d, J= 7.8 Hz, 1H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.61 (s, 1H), 7.38 (t, J= 7.8 Hz, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.38 (dd, J = 10.2, 7.8 Hz,1H), 3.84 (s, 3H), 2.91 - 2.83 (m, 1H), 1.65 (s, 3H), 0.74 (d, J = 7.3Hz, 3H) ppm. 43rel-(2S,3R,4R,5S)-4-[[3-[2-methoxy-3-(trifluoromethyl)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (second eluting isomer by SFCon Lux Cellulose-2 column, rt = 4.18 min) ESI-MS m/z calc. 505.14362,found 506.1 (M+1)⁺; 504.1 (M-1)⁻; Retention time: 3.37 minutes ¹H NMR(400 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.48 (d, J = 5.4 Hz, 1H), 8.29 (d, J= 2.1 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.71 (d, J= 7.8 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.37 (t, J = 7.8 Hz, 1H), 5.15 (d, J= 10.2 Hz, 1H), 4.38 (dd, J = 10.2, 7.8 Hz, 1H), 3.84 (s, 3H), 2.88 (q,J = 7.6 Hz, 1H), 1.65 (s, 3H), 0.74 (d, J = 7.2 Hz, 3H) ppm.

The following compounds were made using a method similar to thatdescribed in Example 1, but without the addition of LiOH/EtOH in step 3.The amide coupling step 4 was carried out using T3P as an activatingagent rather than oxalyl chloride. The purification in step 6 wasconducted by SFC using a Lux i-Cellulose-5 column, 5 µm particle size,25 cm x 10 mm from Phenomenex on an SFC 100 instrument from WatersCorp., on a Minigram SFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 44rel-(2R,3S,4S,5R)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (first eluting isomer by SFCon Lux i-Cellulose-5 column, rt = 2.65 min) ESI-MS m/z calc. 505.14362,found 506.2 (M+1)⁺; 504.2 (M-1)⁻; Retention time: 3.16 minutes ¹H NMR(400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.28 (d, J= 2.2 Hz, 1H), 8.05 (s, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.65 - 7.57(m, 2H), 7.37 - 7.01 (m, 2H), 5.11 (d, J = 10.1 Hz, 1H), 4.29 -4.22 (m,1H), 3.81 (s, 3H), 2.78 (q, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.74 (d, J =7.2 Hz, 3H) ppm. 45rel-(2S,3R,4R,5S)-4-[[3-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (second eluting isomer by SFCon Lux i-Cellulose-5 column, rt = 3.16 min) ESI-MS m/z calc. 505.14362,found 506.1 (M+1)⁺; 504.2 (M-1)⁻; Retention time: 3.16 minutes ¹H NMR(400 MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.28 (d, J= 2.2 Hz, 1H), 8.05 (s, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (s,2H), 7.35 - 7.03 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H), 4.32 - 4.22 (m,1H), 3.81 (s, 3H), 2.78 (dt, J = 14.9, 7.5 Hz, 1H), 1.63 (s, 3H), 0.74(d, J = 7.4 Hz, 3H) ppm.

The following compounds were made using a method similar to thatdescribed in Example 1, except that methylamine was used in place ofammonia in Step 5. In step 6, purification was performed by chiral SFCusing a Chiralpak AS-H column, 5 µm particle size, 25 cm x 10 mm fromDaicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 12rel-(2R,3S,4S,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methylpyridine-2-carboxamide(first eluting isomer by SFC) ESI-MS m/z found 524.5 (M+1)⁺; Retentiontime: 3.33 minutes ¹H NMR (500 MHz, Methanol-d₄) δ 8.51 (d, J = 5.5 Hz,1H), 8.27 (d, J = 2.1 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.37-7.26 (m, 2H), 6.97 (td, J = 73.1, 1.1 Hz, 1H), 5.14 (d, J = 10.4 Hz,1H), 4.41 (dd, J = 10.4, 8.1 Hz, 1H), 2.99 (s, 3H), 2.87 (p, J = 7.6 Hz,1H), 1.71 (d, J = 1.2 Hz, 3H), 0.97 - 0.84 (m, 3H) ppm. 13rel-(2S,3R,4R,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methylpyridine-2-carboxamide (second elutingisomer by SFC) ESI-MS m/z found 524.5 (M+1)⁺; Retention time: 3.33minutes ¹H NMR (500 MHz, Methanol-d₄) δ 8.54 -8.49 (m, 1H), 8.27 (d, J =2.0 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.37 -7.25 (m, 2H), 6.97(td, J = 73.1, 1.1 Hz, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.41 (dd, J =10.4, 8.0 Hz, 1H), 2.99 (s, 3H), 2.87 (p, J = 7.7 Hz, 1H), 1.71 (d, J =1.2 Hz, 3H), 0.93 - 0.86 (m, 3H) ppm.

Example 2 Rel-(2 s,3r,5s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(4) andRel-(2r,3s,5r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(5)

Step 1

To a solution of ethyl 2-diazo-3-oxo-butanoate (5.0 g, 31.4 mmol) in DCM(50 mL) stirring at 0° C. was added triethylamine (8.05 g, 11.2 mL, 78.8mmol). TBSOTf (9.24 g, 8.2 mL, 34.3 mmol) was added slowly and thereaction mixture was stirred for 30 mins at 0° C. The reaction mixturewas washed with 30% NaHCO₃ solution (200 mL). The organic layer wasseparated and washed with water (500 mL) then dried over MgSO₄. Thesolvent was evaporated to give ethyl3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-but-3-enoate (8.22 g, 97%)which was used in the next step without further purification.

Step 2

A solution of 1,1,1-trifluoropropan-2-one (33.8 g, 27 mL, 301.2 mmol) inDCM (150 mL) was stirred at -78° C. and TiCl₄ (56.8 g, 33 mL, 299.2mmol) was added dropwise. The reaction was kept at -78° C. for 10 minbefore a solution of ethyl3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-but-3-enoate (64 g, 236.7 mmol)in DCM (150 mL) was added dropwise. The reaction was kept at -78° C. for1 hour then a saturated solution of NaHCO₃ was added and the mixturediluted with DCM. The organic layer was dried over MgSO₄, concentratedin vacuo and the residue purified by column chromatography (0 to 30%EtOAc in hexane) to give ethyl2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (39 g, 61%)as a pale yellow liquid. ¹H NMR (400 MHz, Chloroform-d) δ 4.92 (s, 1H),4.32 (q, J = 7.1 Hz, 2H), 3.63 (d, J = 15.5 Hz, 1H), 2.84 (d, J = 15.5Hz, 1H), 1.41 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm.

Step 3

Rhodium (II) acetate (643 mg, 1.45 mmol) was charged into an oven driedtwo necked flask. Toluene (970 mL) was added and the solution wasstirred at 100° C. for 10 mins. The solution was briefly lifted out ofthe oil bath whilst a solution of ethyl2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (39 g, 145.4mmol) in a toluene (200 mL) was added dropwise, and the reaction washeated at reflux for 1 hr. The reaction mixture was filtered throughfilter paper and the filtrate was concentrated in vacuo to give ethyl5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (30.89g, 88%). ¹H NMR (400 MHz, Chloroform-d) δ 4.68 (s, 1H), 4.35 - 4.17 (m,2H), 2.89 (d, J = 18.8, 1H), 2.58 (d, J = 18.8, 1H), 1.70 (s, 3H), 1.30(t, J = 7.2, Hz, 3H) ppm.

Step 4

Trifluoromethanesulfonic anhydride (6.0 mL, 35.7 mmol) was addeddropwise to a solution of ethyl5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (6.5 g,27.1 mmol) and DIPEA (14 mL, 80.4 mmol) in DCM (150 mL) at -78° C. andthe reaction stirred for 2.5 hours before saturated aqueous NH₄Cl (75mL) was added. The mixture was warmed to ambient temperature, the layersseparated, and the aqueous layer extracted with DCM (2 × 30 mL). Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo to give ethyl2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(10.1 g, 100%) which was used directly in the next reaction.

Step 5

To a stirred solution of (3,4-difluoro-2-methoxy-phenyl)boronic acid(2.0 g, 10.6 mmol) and ethyl2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(3 g, 7.90 mmol) in toluene (80 mL) was added K₃PO₄ (13 mL of 2 M aq.,26.0 mmol). The mixture was degassed with N₂ for 20 mins beforePd(PPh₃)₄ (466 mg, 0.40 mmol) was added and then heated to 100° C. for 1h. The mixture was filtered by celite pad, the filtrate diluted withwater (50 mL) and the aqueous layer extracted with EtOAc (50 × 2 mL).The organic layer was dried (MgSO₄), filtered and evaporated. Theresidue was purified by column chromatography (SiO₂, 0-2% EtOAc inhexane) to give ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(2.5 g, 85%) as a light-yellow liquid. ¹H NMR (400 MHz, Chloroform-d) δ6.87 (pd, J = 8.8, 6.2 Hz, 2H), 4.15 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H),3.42 (d, J = 17.4 Hz, 1H), 2.93 (d, J = 17.4 Hz, 1H), 1.65 (s, 3H), 1.14(t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z calc. 366.089, found 367.2 (M+1)⁺.

Step 6

EtOH (200 mL) was added to ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(5.51 g, 15.0 mmol) and Pd/C (10 wt. % loading, 2.2 g, 2.067 mmol). Themixture was degassed and stirred under a balloon of H₂ for 96 hours. Thecatalyst was removed by filtration, the solids washed with EtOH (50 mL)and the filtrate concentrated in vacuo. A further portion of Pd/C (10wt. % loading, 2.2 g, 2.07 mmol) was added to the residue followed byEtOH (200 mL) and the reaction mixture stirred under a balloon of H₂ atambient temperature for 24 hours. The catalyst was removed byfiltration, the solids washed with EtOH (50 mL) and the filtrateconcentrated in vacuo. A further portion of Pd/C (10 wt. % loading, 2.2g, 2.07 mmol) was added to the residue followed by EtOH (200 mL) and thereaction mixture stirred under a balloon of H₂ at ambient temperaturefor 4 days. The catalyst was removed by filtration, the solids washedwith EtOH (50 mL) and the filtrate concentrated in vacuo to give ethylrac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(5.19 g, 94%) as a white solid, and as a single diastereomer. ¹H NMR(500 MHz, Chloroform-d) δ 6.89 - 6.86 (m, 1H), 6.82 - 6.77 (m, 1H), 4.93(d, J = 8.9 Hz, 1H), 4.23 (dt, J = 13.0, 7.6 Hz, 1H), 4.08 (d, J = 2.9Hz, 3H), 3.85 - 3.71 (m, 2H), 2.82 (t, J = 12.5 Hz, 1H), 2.04 (dd, J =12.0, 6.7 Hz, 1H), 1.53 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H) ppm; ¹⁹F NMR(471 MHz, Chloroform-d) δ -80.15, -136.84 (d, J = 19.4 Hz), -154.77 (d,J = 19.6 Hz) ppm.

Step 7

Ethylrac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(5.19 g, 14.09 mmol) was dissolved in ethanol (100 mL). Cesium carbonate(7.1 g, 21.8 mmol) was added and the suspension stirred at 50° C. for 2hours. The reaction mixture was concentrated in vacuo and the residuepartitioned between 1 M HCl and MTBE. The layers were separated and theaqueous layer was extracted twice with MTBE. The combined organicextracts were dried (MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (5.11 g, 96%) as a colourless oil, as a single diastereomer. ¹H NMR(500 MHz, Chloroform-d) δ 6.99 - 6.96 (m, 1H), 6.92 -6.87 (m, 1H), 4.68(d, J = 10.5 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 3.90 (ddd, J = 12.0,10.6, 8.2 Hz, 1H), 2.58 (t, J = 12.5 Hz, 1H), 2.31 (dd, J = 13.0, 8.2Hz, 1H), 1.60 (s, 3H) ppm; ¹⁹F NMR (471 MHz, Chloroform-d) δ -81.56,-136.40 (d, J = 19.6 Hz), -153.60 (d, J = 19.5 Hz) ppm. ESI-MS m/z calc.340.0734, found 339.5 (M-1)⁻.

Step 8

To a solution ofrac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (1.5 g, 4.41 mmol) in DCM (30 mL) cooled to -10° C. was added DMF(5 µL, 0.065 mmol) followed by oxalyl chloride (620 µL, 7.11 mmol). Thereaction was stirred for 4 hours, allowing it to warm to ambienttemperature before further oxalyl chloride (300 µL, 3.55 mmol) wasadded. The reaction was stirred for a further hour before beingconcentrated in vacuo. The residue was dissolved in DCM (30 mL) and thesolution cooled in an ice bath. TEA (600 µL, 4.31 mmol) and methyl4-aminopyridine-2-carboxylate (663.7 mg, 4.36 mmol) were addedsequentially and the resultant mixture stirred for 30 mins before beingquenched with MeOH and concentrated in vacuo. Purification by flashchromatography (40 g SiO₂, 0 to 60% ethyl acetate in heptane, loaded inDCM) gave methylrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(827.6 mg, 74%). ¹H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 5.5 Hz,1H), 8.46 (s, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.94 (dd, J = 5.5, 2.2 Hz,1H), 7.00 (ddd, J = 8.0, 5.5, 2.1 Hz, 1H), 6.90 (td, J = 9.1, 7.3 Hz,1H), 4.75 (d, J = 10.7 Hz, 1H), 4.01 (s, 3H), 3.99 (d, J = 2.6 Hz, 3H),3.83 (td, J = 11.4, 8.3 Hz, 1H), 2.61 (t, J = 12.5 Hz, 1H), 2.34 (dd, J= 13.1, 8.2 Hz, 1H), 1.65 (s, 3H) ppm. ESI-MS m/z calc. 474.1214, found474.7 (M+1)⁺ and 473.2 (M-1)⁻.

Step 9

Methylrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(1.9 g, 4.01 mmol) was dissolved in methanolic ammonia (20 mL of 7 M,140.0 mmol) and the reaction stirred at ambient temperature overnight.Additional methanolic ammonia (5 mL of 7 M, 35.0 mmol) was added andreaction stirred at ambient temperature for a further 3 hrs before beingconcentrated in vacuo to giverac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(1.94 g, 99%). ¹H NMR (500 MHz, Methanol-d₄) δ 8.49 (dd, J = 5.5, 0.6Hz, 1H), 8.26 (dd, J = 2.2, 0.6 Hz, 1H), 7.88 (dd, J = 5.5, 2.2 Hz, 1H),7.14 (ddd, J = 8.3, 5.7, 2.3 Hz, 1H), 6.99 (ddd, J = 9.9, 8.9, 7.5 Hz,1H), 4.67 (d, J = 10.3 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.92 (d, J = 2.3Hz, 3H), 3.35 (s, 3H), 2.62 (t, J = 12.4 Hz, 1H), 2.40 (dd, J = 12.8,8.2 Hz, 1H), 1.63 (s, 3H) ppm. ESI-MS m/z calc. 459.12173, found 460.2(M+1)⁺ and 458.3 (M-1)⁻.

Step 10

rac-(2R,3S,5R)-4-[[3-(3,4-Difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(1.9 g, 3.89 mmol) was separated by chiral SFC using a (R,R)-Whelk-O1column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies togive two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 5.05 min):rel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(4, 724 mg, 38%); ESI-MS m/z calc. 459.12173, found 460.2 (M+1)⁺ and458.3 (M-1)⁻. ¹H NMR (500 MHz, Methanol-d₄) δ 8.36 (d, J = 5.5 Hz, 1H),8.13 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 5.5, 2.2 Hz, 1H), 7.00 (ddd, J =8.2, 5.6, 2.2 Hz, 1H), 6.86 (td, J = 9.3, 7.5 Hz, 1H), 4.55 (d, J = 10.3Hz, 1H), 3.92 (ddd, J = 12.2, 10.4, 8.2 Hz, 1H), 3.79 (d, J = 2.3 Hz,3H), 3.22 (s, 1H), 2.49 (t, J = 12.4 Hz, 1H), 2.27 (dd, J = 12.8, 8.2Hz, 1H), 1.50 (s, 3H) ppm.

Second Eluting Isomer (rt = 7.36 min):rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(5, 749 mg, 39%); ESI-MS m/z calc. 459.12173, found 460.2 (M+1)⁺ and458.3 (M-1)⁻. ¹H NMR (500 MHz, Methanol-d₄) δ 8.36 (d, J = 5.5 Hz, 1H),8.13 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 5.5, 2.2 Hz, 1H), 7.01 (ddd, J =8.3, 5.6, 2.2 Hz, 1H), 6.86 (td, J = 9.4, 7.5 Hz, 1H), 4.55 (d, J = 10.2Hz, 1H), 3.92 (ddd, J = 12.0, 10.4, 8.2 Hz, 1H), 3.79 (d, J = 2.3 Hz,3H), 3.22 (s, 3H), 2.49 (t, J = 12.4 Hz, 1H), 2.27 (dd, J = 12.9, 8.2Hz, 1H), 1.50 (s, 3H) ppm.

The following compounds were made using a method similar to thatdescribed Example 2, except that 5-amino-2-fluorobenzamide was used ascoupling partner in step 8, and step 9 was omitted:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 46rel-(2S,3R,5S)-N-(3-carbarnoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (first eluting isomer by SFC on Whelk01 column, rt =0.90 min) ESI-MS m/z calc. 476.11707, found 477.1 (M+1)⁺; 475.3 (M-1)⁻;Retention time: 3.09 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.44 (s,1H), 8.18 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 7.89 (dd, J = 6.6, 2.9 Hz,1H), 7.10 (dd, J = 11.3, 9.0 Hz, 1H), 7.01 (ddd, J = 8.8, 5.6, 2.2 Hz,1H), 6.89 (td, J = 9.2, 7.3 Hz, 1H), 6.71 (d, J = 11.8 Hz, 1H), 5.91 (s,1H), 4.73 (d, J = 10.7 Hz, 1H), 3.97 (d, J = 2.5 Hz, 3H), 3.82 (td, J =11.4, 8.3 Hz, 1H), 3.49 (d, J = 4.4 Hz, 1H), 2.57 (t, J = 12.5 Hz, 1H),2.32 (dd, J = 13.0, 8.2 Hz, 1H), 1.64 (s, 3H) ppm. 47rel-(2R,3S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (second eluting isomer by SFC on Whelk01 column, rt =1.35 min) ESI-MS m/z calc. 476.11707, found 477.1 (M+1)⁺; 475.3 (M-1)⁻;Retention time: 3.09 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.42 (s,1H), 8.18 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 7.89 (dd, J = 6.6, 2.9 Hz,1H), 7.11 (dd, J = 11.2, 9.0 Hz, 1H), 7.01 (ddd, J = 8.1, 5.5, 2.2 Hz,1H), 6.89 (td, J = 9.1, 7.3 Hz, 1H), 6.71 (d, J = 11.8 Hz, 1H), 5.88 (s,1H), 4.73 (d, J = 10.7 Hz, 1H), 3.97 (d, J = 2.5 Hz, 3H), 3.82 (td, J =11.4, 8.3 Hz, 1H), 2.57 (t, J = 12.5 Hz, 1H), 2.32 (dd, J = 13.1, 8.2Hz, 1H), 1.64 (s, 3H) ppm.

Example 3(2s,3r,4r,5s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(6) and(2r,3s,4s,5r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(7)

Step 1

NEt₃ (7.7 mL, 55.2 mmol) was added to a solution of ethyl2-diazo-3-oxo-pentanoate (6.69 g, 39.3 mmol) in DCM (80 mL) withstirring at 0° C. under nitrogen. Trimethylsilyltrifluoromethanesulfonate (8.5 mL, 47.0 mmol) was added dropwise over 5mins and the mixture was stirred for a further 30 mins at 0° C. Thereaction mixture was diluted with pentane (100 mL), the layers separatedand the organic phase washed with dilute aqueous sodium bicarbonate (100mL) and brine (100 mL). The organic layer was dried (MgSO₄), andconcentrated in vacuo to give ethyl(Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (9.4 g, 99%) as a red oil.¹H NMR (500 MHz, Chloroform-d) δ 5.33 (q, J = 7.0 Hz, 1H), 4.25 (q, J =7.1 Hz, 2H), 1.67 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.22(s, 9H) ppm.

Step 2

To a solution of 1,1,1-trifluoropropan-2-one (8 mL, 89.4 mmol) in DCM(80 mL) stirring at -78° C. was added TiCl₄ (70 mL of 1 M in DCM, 70.00mmol) via cannula. To the resulting solution, a solution of ethyl(Z)-2-diazo-3-trimethylsilyloxy-pent-3-enoate (36.1 g of 31.3 %w/w, 46.6mmol) in 40 mL of DCM was added dropwise over 15 mins. After 100 minsthe reaction was carefully quenched with water, allowing the temperatureto rise slowly, and then extracted with DCM. The combined organic layerswere dried (MgSO₄), filtered, and concentrated in vacuo. Purification byflash chromatography (330 g SiO₂, 0 to 20% EtOAc in heptane) gave ethyl2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (8.82 g,67%), which was stored as a solution in toluene. ¹H NMR (500 MHz,Chloroform-d) δ 4.33 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.0 Hz, 1H), 3.98(s, 1H), 1.43 (q, J = 1.2 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.31 (dq, J= 7.0, 1.4 Hz, 3H) ppm. ESI-MS m/z calc. 282.08273, found 283.1 (M+1)⁺;281.0 (M-1)⁻.

Step 3

A solution of rhodium tetraacetate (245 mg, 0.55 mmol) in benzene (32mL) was heated at reflux for 10 min before a solution of ethyl2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (10 g,35.4 mmol) in benzene (13 mL) was added slowly via addition funnel whilerefluxing for 60 mins. The mixture was then concentrated in vacuo togive ethylrac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(9.0 g, 100%) as a green coloured residue containing residual catalyst,and as a mixture of epimers at the position next to the ester. Thismaterial was used without further purification. ¹H NMR (500 MHz,Chloroform-d) δ 4.83 - 4.57 (m, 1H), 4.38 - 4.16 (m, 2H), 2.60 (dddd, J= 9.3, 8.2, 5.6, 1.4 Hz, 1H), 1.73 - 1.63 (m, 3H), 1.30 (t, J = 7.1 Hz,3H), 1.24 (ddq, J = 6.4, 4.1, 1.9 Hz, 3H) ppm.

Step 4

To a stirred solution of ethylrac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(48 g, 188.83 mmol) in DCM (400 mL) stirring at -78° C. was added DIPEA(29.680 g, 40 mL, 229.64 mmol). A solution of trifluoromethylsulfonyltrifluoromethanesulfonate (53.440 g, 32 mL, 189.41 mmol) in DCM (200 mL)was added to the reaction mixture at the same temperature over 1 h. Thereaction mixture was stirred for 30 mins at 0° C. before being quenchedwith 100 mL saturated aqueous NaHCO₃ solution. The organic layer wasseparated and aqueous layer extracted with DCM (160 mL). The combinedorganic layers were dried (MgSO₄) and concentrated in vacuo to giveethylrac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(71 g, 97%). ¹H NMR (400 MHz, Chloroform-d) δ 4.38-4.32 (m, 2H),3.29-3.23 (m, 1H), 1.64 (s, 3H), 1.37-1.33 (m, 6H) ppm.

Step 5

To stirred a solution of ethylrac-(4R,5R)-2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(26 g, 67.311 mmol) in toluene (130.00 mL) was added(3,4-difluoro-2-methoxy-phenyl)boronic acid (14 g, 74.5 mmol) followedby K₃PO₄ (100 mL of 2 M, 200.00 mmol) under an argon atmosphere. Thereaction was degassed before tetrakis(triphenylphosphine)palladium(0) (4g, 3.46 mmol) was added. After further degassing, the reaction washeated at 100° C. for 2 hours. The reaction was diluted in water and theaqueous layer extracted with EtOAc (2 ×100 mL). The combined organiclayers were concentrated in vacuo. Purification by flash chromatography(SiO₂, 0 to 10% EtOAc in heptane) gave ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(24.4 g, 93%) as a 6:1 diastereomeric mixture, with the major isomerbelieved to be ethylrac-(4R,5R)-4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate.Major isomer: ¹H NMR (400 MHz, Chloroform-d) δ 6.88 - 6.79 (m, 2H),4.17 - 4.09 (m, 2H), 3.90 (s, 3H), 3.46 (q, J = 7.4 Hz, 1H), 1.67 (s,3H), 1.12 (t, J = 7.4 Hz, 3H), 1.06 (dd, J = 5.4, 2.7 Hz, 3H) ppm. Minorisomer ¹H NMR (400 MHz, Chloroform-d) δ 6.88 - 6.79 (m, 2H), 4.17-4.09(m, 2H), 3.88(s, 3H), 3.76-3.71(m, 1H), 1.51 (s, 3H), 1.12 (t, J = 7.4Hz, 3H), 0.99 (dd, J = 5.4, 2.7 Hz, 3H) ppm. ESI-MS m/z calc. 380.1047,found 381.02 (M+1)⁺.

Step 6

To an ice-cooled solution of ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(110 g, 243.0 mmol) in DCM (360 mL) was added BBr₃ (370 mL of 1 M, 370.0mmol) dropwise. Upon completion the mixture was quenched by addition ofwater and aqueous sodium bicarbonate solution, the aqueous layerextracted with DCM and the combined organic layers dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in DCM (430 mL) atambient temperature and TFA (40 mL, 519.2 mmol) was added, then thereaction was heated to 45° C. Upon completion, the mixture was quenchedby addition of aqueous sodium bicarbonate solution and the aqueous layerextracted with DCM, dried (MgSO₄) and concentrated in vacuo to give thedesired product in a 5:1 mixture of diastereomers. Recrystallization wascarried out by solubilizing the crude in the smallest possible amount ofDCM and adding a layer of heptane on top of this solution (liquid-liquiddiffusion). After approx. 1 hour, 56.5 g (d.r. 97:3 syn:anti) from thefirst and second crystallization was obtained, and a further 4.6 g (d.r.96:4 syn:anti) from the third crystallization was obtained. The first tothird batches were combined to give6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one(61 g, 78%), with the major isomer believed to berac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one.ESI-MS m/z calc. 320.04718, found 321.5 (M+1)⁺; 319.6 (M-1)⁻.

Step 7

rac-(1S,2R)-6,7-Difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one(30 g, 93.69 mmol) was dissolved in EtOAc (400 mL) and stirred withactivated charcoal (6 g, 499.6 mmol) (0.2 g/g of substrate) at ambienttemperature for 4 hours and 30 minutes. The mixture was filtered througha pad of celite, washing with EtOAc. The filtrate was concentrated invacuo to give a white solid. The white solid was suspended in MeOH (600mL) and added to a suspension of Pd(OH)₂ (13.62 g of 20% w/w, 19.40mmol) in MeOH (150 mL) in a 2.25 L Parr bottle. The resulting mixturewas shaken in the Parr hydrogenator under a hydrogen pressure of 60 psiovernight. The suspension was filtered through celite under a nitrogenatmosphere, rinsed with MeOH and then with EtOAc, and the resultingfiltrate was concentrated in vacuo to give methylrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(32.75 g, 99%). ¹H NMR (400 MHz, Methanol-d4) δ 7.05 (ddq, J = 9.4, 5.9,1.9 Hz, 1H), 6.57 (ddd, J = 10.0, 9.0, 7.6 Hz, 1H), 5.01 (d, J = 6.0 Hz,1H), 4.34 (dd, J = 8.4, 6.0 Hz, 1H), 3.49 (s, 3H), 3.01 - 2.86 (m, 1H),1.50 (q, J = 1.2 Hz, 3H), 0.89 (dq, J = 7.6, 1.9 Hz, 3H) ppm. ESI-MS m/zcalc. 354.08905, found 353.3 (M-1)⁻.

Step 8

A solution of methylrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(60.8 g, 171.6 mmol) in THF (620 mL) was cooled to 1° C., and potassiumtert-butoxide (65.0472 g, 579.7 mmol) was added over 10 mins, keepingthe internal temperature below 10° C. The mixture was stirred at 0° C.for a further 5 min, and then the mixture was warmed slightly. When thetemperature had reached 13° C., the reaction was cooled down again withan ice bath before adding 2 M HCl (365 mL, to pH 1), keeping theinternal temperature below 15° C. Water (300 mL) was added, the layerswere separated, and the aqueous layer was extracted with EtOAc (110 mL).The combined organic extracts were washed with brine (300 mL), dried(MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (58.22 g, 100%). ¹H NMR (400 MHz, Methanol-d₄) δ 7.00 (ddd, J =8.4, 5.6, 2.3 Hz, 1H), 6.69 (ddd, J = 10.1, 8.8, 7.5 Hz, 1H), 4.98 (d, J= 10.5 Hz, 1H), 4.18 (dd, J = 10.5, 7.6 Hz, 1H), 2.83 (p, J = 7.5 Hz,1H), 1.59 (q, J = 1.2 Hz, 3H), 0.76 (dq, J = 7.2, 2.2 Hz, 3H) ppm.ESI-MS m/z calc. 340.0734, found 339.0 (M-1)⁻.

Step 9

To a solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (58.39 g, 171.6 mmol) in acetonitrile (300 mL) was added K₂CO₃(82.6 g, 597.7 mmol) and MeI (37 mL, 594.3 mmol). The reaction washeated to 80° C. (internally temperature reached 61° C.) for 5 hoursbefore being cooled to ambient temperature and diluted with DCM (350mL). The mixture was filtered, washing the filter cake with more DCM(350 mL) and the filtrate was concentrated in vacuo to give methylrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(64.7 g, 100%) as an orange oil containing some residual K₂CO₃. Thismaterial was used in the next step without further purification. ¹H NMR(400 MHz, Chloroform-d) δ 6.91 (ddd, J = 7.6, 5.7, 1.9 Hz, 1H), 6.85(td, J = 9.1, 7.2 Hz, 1H), 4.91 (d, J = 10.2 Hz, 1H), 4.13 (dd, J =10.2, 8.0 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 3.71 (s, 3H), 2.72 (p, J =7.7 Hz, 1H), 1.62 (q, J = 1.2 Hz, 3H), 0.76 (dq, J = 7.5, 2.4 Hz, 3H)ppm.

Step 10

Methylrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(63.2 g, 171.6 mmol) was dissolved in MeOH (500 mL) and water (300 mL).LiOH·H₂O (14.8882 g, 354.8 mmol) was added and the resultant mixturestirred at ambient temperature for 2 hours. The MeOH was removed invacuo and the mixture was diluted in MTBE (320 mL). 2 M HCl (440 mL) wasadded to reach pH 1, the layers were separated and the aqueous layerextracted twice with MTBE (100 mL). The combined organic layers weredried (MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (60.3 g, 99%) as an orange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 12.96(s, 1H), 7.40 - 6.82 (m, 2H), 4.96 (dd, J = 15.5, 10.5 Hz, 1H), 4.08(dd, J = 10.4, 7.6 Hz, 1H), 3.93 (d, J = 2.2 Hz, 3H), 2.67 (p, J = 7.7Hz, 1H), 1.59 - 1.49 (m, 3H), 0.77 - 0.63 (m, 3H) ppm. ESI-MS m/z calc.354.08905, found 353.1 (M-1)⁻.

Step 11

To a solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (158.6 g, 447.7 mmol) and DMF (135 µL, 1.74 mmol) in DCM (1.5 L)stirring at 0° C. under nitrogen was added oxalyl chloride (79 mL, 905.6mmol) via dropping funnel, over 30 mins. Halfway through addition theice bath was removed and the mixture allowed to warm ambient temperatureover the remainder of the addition. The mixture was stirred at ambienttemperature for a further 1 hour before being evaporated in vacuo. Theresidue was dissolved in DCM (700 mL) and added via dropping funnel to asolution of methyl 4-aminopyridine-2-carboxylate (81.5 g, 535.7 mmol),DMF (135 µL, 1.744 mmol) and Et₃N (95 mL, 681.6 mmol) in DCM (780 mL)stirring at -10° C. The rate of addition was controlled so as to keepinternal temperature below 5° C. (~15 mins). Following addition, themixture was diluted in water (600 mL), the layers were separated and theaqueous phase was further extracted with DCM (100 mL). Solid formed atthe interface between the layers and was collected by filtration toprovide filtered desired product (43.2 g). The filtrate was washedfurther with water (600 mL), dried (MgSO₄), filtered and concentrated invacuo. The residue was suspended in MeOH (360 mL) and stirred rapidlyfor 20 mins. The mixture was filtered and the solid washed with MeOH anddried under vacuum for 30 mins. This material was combined with thepreviously obtained product to give methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(166.2 g, 76%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.74 (s,1H), 8.57 (d, J = 5.4 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.85 (dd, J =5.5, 2.2 Hz, 1H), 7.16 (qd, J = 9.2, 6.3 Hz, 2H), 5.11 (d, J = 10.1 Hz,1H), 4.25 (dd, J = 10.2, 7.7 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.87 (s,3H), 2.77 (p, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.81 - 0.65 (m, 3H) ppm.ESI-MS m/z calc. 488.13705, found 489.6 (M+1)⁺; 487.6 (M-1)⁻.

Step 12

Methanolic ammonia (3 L of 7 M, 21.00 mol) was added to methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(166 g, 339.9 mmol) and the reaction stirred at ambient temperatureovernight. The mixture was concentrated in vacuo to giverac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(173 g) as an off-white solid, which was used in the next step withoutfurther purification. ESI-MS m/z calc. 473.1374, found 474.6 (M+1)⁺;472.6 (M-1)⁻.

Step 13

rac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(670 mg, 1.415 mmol) was purified by chiral SFC (using a (R′R) Whelk O-1column, 3-5 µm particle size, 5.0 cm x 3.0 mm from Regis Technologieswith Solvent A: liquid CO₂ [58-60 bar/40° C.; Solvent B: methanol HPLCgrade with 20 mM NH₃ on a UPC2-SFC instrument from Waters Corp.) togive:

First Eluting Isomer:(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(6, 198 mg): ¹H NMR (500 MHz, Methanol-d₄) δ 8.52 (d, J = 5.5 Hz, 1H),8.30 (d, J = 2.0 Hz, 1H), 7.94 (dd, J = 5.5, 2.2 Hz, 1H), 7.16 (ddd, J =8.2, 5.6, 2.3 Hz, 1H), 7.02 (ddd, J = 9.9, 8.9, 7.5 Hz, 1H), 5.12 (d, J= 10.4 Hz, 1H), 4.37 (dd, J = 10.4, 8.0 Hz, 1H), 4.03 (d, J = 2.2 Hz,3H), 2.84 (p, J = 7.6 Hz, 1H), 1.70 (d, J = 1.1 Hz, 3H), 0.86 (dq, J =7.4, 2.4 Hz, 3H) ppm. ESI-MS m/z calc. 473.1374, found 474.6 (M+1)⁺;472.7 (M-1)⁻.

Second Eluting Isomer:(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(7, 195 mg): ¹H NMR (500 MHz, Methanol-d₄) δ 8.39 (d, J = 5.5 Hz, 1H),8.16 (d, J = 2.0 Hz, 1H), 7.80 (dd, J = 5.5, 2.0 Hz, 1H), 7.02 (ddd, J =8.2, 5.7, 2.4 Hz, 1H), 6.88 (ddd, J = 9.9, 8.8, 7.5 Hz, 1H), 4.98 (d, J= 10.4 Hz, 1H), 4.23 (dd, J = 10.4, 7.9 Hz, 1H), 3.89 (d, J = 2.2 Hz,3H), 2.70 (p, J = 7.6 Hz, 1H), 1.56 (d, J = 1.1 Hz, 3H), 0.72 (dq, J =7.6, 2.4 Hz, 3H) ppm. ESI-MS m/z calc. 473.1374, found 474.6 (M+1)⁺;472.8 (M-1)⁻.

The absolute stereochemistry of 6 and 7 was determined by single-crystalX-ray crystallography of 7.

Compound 7 - Solid Form A

Crystallization of Compound 7 in methanol at 60° C. produced acrystalline form of Compound 7, which is referred to herein as Form A.Form A was characterized by XRPD, TGA, and DSC analysis.

The XRPD pattern of Form A is depicted in FIG. 1 , and the correspondingdata are summarized in the following table:

Angle (° 2θ ± 0.2) Rel. Intensity (%) 7.3 19.9 9.9 28.3 13.9 100.0 15.720.1 19.0 50.4 20.1 31.8 20.3 19.3 25.4 14.7

The TGA thermogram of Form A is depicted in FIG. 2 and shows negligibleweight loss from ambient temperature up until thermal degradation.

The DSC thermogram of Form A is depicted in FIG. 3 and shows a meltingonset of 186° C. with a peak at 187° C.

Compound 7 - Solid Form B

Compound 7 was dissolved in ethyl acetate (6 volumes) at 68° C. Themixture was cooled to 50° C. over 1 hour, and n-heptane (6 volumes) wasadded over 5 hours. The mixture was then cooled to 20° C. over a further5 hours and held overnight. The resulting solid material was filtered,washed with heptane (3 volumes), and dried to produce a crystalline formof Compound 7, which is referred to herein as Form B. Form B wascharacterized by XRPD, solid state NMR (¹³C and ¹⁹F), TGA, DSC, IR, andsingle-crystal X-ray analysis.

The XRPD pattern of Form B is depicted in FIG. 4 , and the correspondingdata are summarized in the following table:

Angle (° 2θ ± 0.2) Rel. Intensity (%) 7.6 11.3 9.2 10.5 12.0 10.0 12.836.7 14.1 59.3 15.1 24.0 15.2 39.4 16.2 23.9 16.9 31.9 17.6 15.1 18.463.1 18.5 100.0 18.7 51.7 19.3 64.2 20.3 64.6 21.7 11.6 22.0 29.3 22.229.7 22.9 15.1 23.6 27.3 24.0 10.9 24.2 16.8 25.2 30.0 26.9 15.6 27.010.7 27.4 17.0 28.6 10.8 28.9 20.9

The solid state ¹³C NMR spectrum of Form B is depicted in FIG. 5 , andthe corresponding data are summarized in the following table:

Chemical Shift [ppm] Rel. Intensity (%) 172.5 23.1 172.1 29.4 168.5 18.8168.3 17.8 168.0 20.1 151.5 36.8 148.3 100.0 147.8 35.0 127.7 83.3 122.770.4 116.6 53.1 115.1 44.5 110.6 51.6 86.5 13.0 80.2 60.4 63.2 42.3 44.399.1 23.0 51.8 13.1 51.7

The solid state ¹⁹F NMR spectrum of Form B is depicted in FIG. 6 , andthe corresponding data are summarized in the following table:

Chemical Shift [ppm] Rel. Intensity -137.1 12.5 -152.8 5.8

The TGA thermogram of Form B is depicted in FIG. 7 and shows negligibleweight loss from ambient temperature up until thermal degradation.

The DSC thermogram of Form B is depicted in FIG. 8 and shows a meltingonset of 182° C. with a peak at 183° C.

The IR spectrum of Form B is depicted in FIG. 9 and includes peaks at3501, 3356, 1684, 1565, 1505, and 1122 cm⁻¹.

Crystals having Form B were grown for single-crystal X-ray analysis bydissolving 1 mg of Compound 7 material in 500 µL of ethanol, which wasallowed to evaporate slowly over several days. The thermal ellipsoidplot, at 50% probability, is depicted in FIG. 10 , and the unit cellparameters are reported in the following table:

Crystal System: Orthorhombic Space Group: P2₁2₁2₁ a (Å) 7.3929(2) b (Å)14.5827(4) c (Å) 18.9312(6) α (°) 90 β (°) 90 γ (°) 90 V (Å³)2040.94(10) Z 4 Temperature 100 K

The following compounds were made using a similar method to that ofExample 3 and were separated by chiral SFC using a (R,R)-Whelk-O1column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies :

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 8(2S,3R,4R,5S)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (first eluting isomer by SFC,rt = 3.76 min) ESI-MS m/z found 488.35 (M+1)⁺; Retention time: 3.355minutes ¹H NMR (500 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.50 (dd, J = 5.5,0.6 Hz, 1H), 8.28 (dd, J = 2.2, 0.6 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H),7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 7.20 -7.15 (m,2H), 5.11 (d, J = 10.4 Hz, 1H), 4.30 (dd, J = 10.4, 7.5 Hz, 1H), 4.24 -4.12 (m, 2H), 2.76 (p, J = 7.5 Hz, 1H), 1.62 (s, 3H), 1.36 (t, J = 7.0Hz, 3H), 0.74 (dd, J = 7.6, 2.4 Hz, 3H) ppm. 9(2R,3S,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (second eluting isomer by SFC,rt = 8.22 min) ESI-MS m/z found 488.35 (M+1)⁺; Retention time: 3.355minutes ¹H NMR (500 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.50 (dd, J = 5.5,0.6 Hz, 1H), 8.28 (dd, J = 2.2, 0.7 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H),7.83 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.20 -7.14 (m,2H), 5.11 (d, J = 10.4 Hz, 1H), 4.30 (dd, J = 10.4, 7.6 Hz, 1H), 4.24 -4.12 (m, 2H), 2.76 (p, J = 7.5 Hz, 1H), 1.62 (s, 3H), 1.36 (t, J = 7.0Hz, 3H), 0.74 (dd, J = 7.6, 2.4 Hz, 3H) ppm.

Compound 9 - Solid Form A

A crystalline form of Compound 9, referred to herein as Form A, wasobtained and was characterized by single-crystal X-ray analysis.Crystals having Form A were grown for single-crystal X-ray analysis bydissolving ~1 mg of Compound 9 material in 350 µL of 10/90dichloromethane/dichloroethane solution, which was then vapor diffusedwith pentane over several days. The thermal ellipsoid plot, at 50%probability, is depicted in FIG. 11 , and the unit cell parameters arereported in the following table:

Crystal System: Orthorhombic Space Group: I222 a (Å) 12.0172(5) b (Å)15.6682(6) c (Å) 24.1406(11) α (°) 90 β (°) 90 γ (°) 90 V (Å³) 4545.4(3)Z 8 Temperature 100 K

The following compound was made from(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid, which can be obtained by separating the enantiomers of the6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-oneobtained in Step 6 using the SFC conditions described in Step 1 ofExample 23, and using the resulting optically pure material in steps 7and 8 of Example 3, by a method similar to that described in Steps 9-12of Example 3, using CD₃I in place of MeI in Step 9:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 264-[[(2R,3S,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z found 477.6 (M+1)⁺;Retention time: 3.24 minutes ¹H NMR (500 MHz, DMSO-d₆) δ 10.71 (s, 1H),8.49 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 7.83(dd, J = 5.5, 2.2 Hz, 1H), 7.60 (s, 1H), 7.17 (dd, J = 9.6, 6.2 Hz, 2H),5.10 (d, J = 10.2 Hz, 1H), 4.26 (dd, J = 10.2, 7.7 Hz, 1H), 2.78 (p, J =7.6 Hz, 1H), 1.61 (s, 3H), 0.73 (d, J = 7.5 Hz, 3H) ppm.

The following compounds were prepared by methods similar to the methodsdescribed herein:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 484-[[(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ10.29 (s, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.20 (d, J = 1.5 Hz, 1H), 8.02(br s, 1H), 7.70 (dd, J = 5.4, 1.9 Hz, 1H), 7.58 (br s, 1H), 7.24 -7.17(m, 1H), 6.99 (q, J = 9.1 Hz, 1H), 5.12 (d, J = 5.9 Hz, 1H), 4.37 - 4.25(m, 1H), 3.89 (s, 3H), 2.98 (quin, J = 7.5 Hz, 1H), 1.54 (s, 3H), 0.75(br d, J = 6.7 Hz, 3H) ppm. 494-[[(2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ¹H NMR (400 MHz, DMSO-d₆) δ10.20 (s, 1H), 8.39 (d, J = 5.5 Hz, 1H), 8.02 (br d, J = 2.1 Hz, 1H),7.98 (d, J = 2.0 Hz, 1H), 7.65 - 7.53 (m, 1H), 7.48 (dd, J = 2.2, 5.5Hz, 1H), 7.00 - 6.90 (m, 2H), 4.85 (d, J = 8.9 Hz, 1H), 3.98 (d, J = 2.0Hz, 3H), 3.93 (dd, J = 9.1, 13.0 Hz, 1H), 2.99 (br qd, J = 6.7, 12.7 Hz,1H), 1.68 (s, 3H), 0.98 (br d, J = 6.5 Hz, 3H) ppm. 504-[[(2R,3S,4R,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 473.4, found474.2 (M+H)⁺; Retention time: 8.9 minutes ¹H NMR (400 MHz, Chloroform-d)δ 8.83 (s, 1H), 8.45 (d, J= 5.6 Hz, 1H), 8.19 (dd, J= 5.6, 2.3 Hz, 1H),8.03 (dd, J = 2.2, 0.4 Hz, 1H), 7.84 (br d, J = 3.8 Hz, 1H), 6.98 -6.88(m, 2H), 5.80 (br d, J= 3.9 Hz, 1H), 4.68 (d, J= 10.6 Hz, 1H), 3.94 (d,J= 2.4 Hz, 3H), 3.41 (t, J = 11.3 Hz, 1H), 2.93 -2.84 (m, 1H), 1.53 (s,3H), 0.98 (d, J = 6.8 Hz, 3H) ppm.

Example 4(2s,3r,4r,5s)-4-[[3-[2-(Difluoromethoxy)-3,4-Difluoro-Phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(10) and(2r,3s,4s,5r)-4-[[3-[2-(Difluoromethoxy)-3,4-Difluoro-Phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]pyridine-2-Carboxamide(11)

Step 1

To a solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (9.30 g, 27.33 mmol, prepared as described in Example 3, Step 8) inDCM (50 mL) stirring at 0° C. was added a solution of KOH (18.4 g, 328.0mmol) in H₂O (50 mL) and the solution stirred vigorously.[Bromo(difluoro)methyl]-trimethyl-silane (22.5 g, 110.8 mmol) was addedand stirring continued at this temperature. Upon complete consumption ofstarting material, the mixture was acidified by addition of 1 N HCl,extracted with DCM and concentrated in vacuo. The resultant oil wasdissolved in tert-butanol (50 mL) at ambient temperature and KOt-Bu (7.5g, 66.84 mmol) was added. After complete conversion the mixture wasacidified with 1 N HCl, diluted with DCM, the layers separated and theaqueous layer extracted. The organic phase was washed with waterconcentrated in vacuo to giverac-(2R,3S,4S,5R)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (10.10 g, 95%) which was used without further purification.

Step 2

To an ice-cooled solution ofrac-(2R,3S,4S,5R)-3-[2-(difluoromethoxy)-3,4-difluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (10.10 g, 25.88 mmol) in DCM (100 mL) stirring at 0° C., DMF (400µL, 5.17 mmol) and oxalyl chloride (4.85 mL, 55.60 mmol) were added. Themixture was warmed to ambient temperature over 30 min before beingconcentrated in vacuo. The solids were dissolved in DCM (80 mL) and DMF(400 µL, 5.17 mmol) and the solution added to an ice cooled solution ofmethyl 4-aminopyridine-2-carboxylate (4.05 g, 26.62 mmol) and NEt₃ (4.5mL, 32.29 mmol) in DCM (80 mL). The reaction was warmed to ambienttemperature over 2 hours then quenched by addition of water (1 drop) andMeOH (2 mL) and concentrated in vacuo. Purification by flashchromatography (4 g SiO₂, 0 to 100% EtOAc in petroleum ether) gavemethylrac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(5.4 g, 40%). ESI-MS m/z calc. 524.1182, found 523.6 (M-1)⁻.

Step 3

Methylrac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(5.50 g, 10.49 mmol) was dissolved in MeOH (300 mL) and methanolicammonia (300 mL of 3.37 M, 1.01 mol) and stirred at ambient temperatureovernight before the reaction mixture was concentrated in vacuo toaffordrac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(115, 5.18 g, 97%). ¹H NMR (500 MHz, Methanol-d₄) δ 8.38 (d, J = 5.6 Hz,1H), 8.15 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 5.5, 2.2 Hz, 1H), 7.23 -7.10 (m, 2H), 6.83 (td, J = 73.1, 1.0 Hz, 1H), 4.99 (d, J = 10.3 Hz,1H), 4.27 (dd, J = 10.4, 8.1 Hz, 1H), 2.73 (p, J = 7.7 Hz, 1H), 1.56 (d,J = 1.2 Hz, 3H), 0.78 - 0.72 (m, 3H) ppm. ESI-MS m/z calc. 509.11856,found 510.5 (M+1)⁺; 508.6 (M-1)⁻.

Step 4

Purification ofrac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(82 mg, 0.1562 mmol) by chiral SFC [System: (R,R)-Whelk-O1 column, 5 µmparticle size, 25 cm × 21.2 mm from Regis Technologies, MeOH, 20 mM NH₃]gave:

First Eluting Isomer:(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(10, 23 mg). ¹H NMR (500 MHz, Methanol-d₄) δ 8.53 (d, J = 5.5 Hz, 1H),8.30 (dd, J = 2.2, 0.6 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H), 7.40 -7.23 (m, 2H), 6.97 (td, J = 73.1, 1.0 Hz, 1H), 5.14 (d, J = 10.4 Hz,1H), 4.41 (dd, J = 10.3, 8.1 Hz, 1H), 2.87 (p, J = 7.7 Hz, 1H), 1.71 (d,J = 1.3 Hz, 3H), 0.94 - 0.81 (m, 3H) ppm. ESI-MS m/z calc. 509.11856,found 510.4 (M+1)⁺; 508.4 (M-1)⁻.

Second Eluting Isomer:(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(11, 28 mg, 70%). ¹H NMR (500 MHz, Methanol-d₄) δ 8.53 (d, J = 5.5 Hz,1H), 8.30 (dd, J = 2.2, 0.6 Hz, 1H), 7.93 (dd, J = 5.5, 2.2 Hz, 1H),7.40 - 7.23 (m, 2H), 6.97 (td, J = 73.1, 1.0 Hz, 1H), 5.14 (d, J = 10.4Hz, 1H), 4.41 (dd, J = 10.3, 8.1 Hz, 1H), 2.87 (p, J = 7.7 Hz, 1H), 1.71(d, J = 1.3 Hz, 3H), 0.94 - 0.81 (m, 3H) ppm. ESI-MS m/z calc.509.11856, found 510.4 (M+1)⁺, 508.4 (M-1)⁻.

The absolute stereochemistry of 10 and 11 was determined bysingle-crystal X-ray crystallography of 11.

Compound 11 - Solid Form A

Compound 11 was suspended in distilled water, the suspension was stirredat 37° C. for 24 hours, at which time the suspension wasfilter-centrifuged. The resulting solid was dried at 60° C. overnight ina vacuum oven to afford a crystalline form of Compound 11, which isreferred to herein as Form A. Form A was characterized by XRPD analysis.

The XRPD pattern of Form A is depicted in FIG. 12 , and thecorresponding data are summarized in the following table:

Angle (° 2θ ± 0.2) Rel. Intensity (%) 7.1 12.0 7.3 29.0 10.1 43.2 13.7100.0 14.1 76.7 16.0 23.0 16.3 65.6 17.6 10.3 18.5 17.0 18.9 11.5 20.046.5 20.4 18.5 21.5 15.2 23.7 22.9 24.8 27.3 25.7 12.7 26.1 13.9

Compound 11 - Solid Form B

Compound 11 was recrystallized from acetonitrile and dried overnight toproduce a crystalline form of Compound 11, which is referred to hereinas Form B. Form B was characterized by XRPD and single-crystal X-rayanalysis.

The XRPD pattern of Form B is depicted in FIG. 13 , and thecorresponding data are summarized in the following table:

Angle (° 2θ ± 0.2) Rel. Intensity (%) 6.8 36.4 11.5 26.7 13.2 100.0 13.618.3 14.4 19.8 15.6 12.0 16.1 40.5 16.3 28.2 17.6 14.0 18.0 13.2 18.823.9 19.4 16.6 20.6 48.1 21.3 67.5 22.3 11.2 23.3 10.8 24.2 12.1 27.49.8

Crystals having Form A were grown for single-crystal X-ray analysis byconcentration of a toluene solution of Compound 11. The thermalellipsoid plot, at 50% probability, is depicted in FIG. 14 , and theunit cell parameters are reported in the following table:

Crystal System: Monoclinic Space Group: P2₁ a (Å) 12.0863(2) b (Å)7.48310(10) c (Å) 23.9904(4) α(°) 90 β(°) 90.0130(10) γ (°) 90 V (Å³)2169.76(6) Z/Z′ 2/0.5 Temperature 100(2)K

The following compounds were made using a method similar to thatdescribed in Example 4, except that 5-amino-2-fluorobenzamide was usedin place of methyl 4-aminopyridine-2-carboxylate in Step 2, and Step 3was omitted. In step 4, purification was performed by chiral SFC using a(R,R)-Whelk-O1 column, 5 µm particle size, 25 cm × 21.2 mm from RegisTechnologies:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 14rel-(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(first eluting isomer by SFC) ESI-MS m/z found 527.1 (M+1)⁺; Retentiontime: 3.23 minutes ¹H NMR (500 MHz, Methanol-d₄) δ 7.96 (dd, J = 6.5,2.8 Hz, 1H), 7.77 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.35 - 7.24 (m, 2H),7.19 (dd, J = 10.5, 9.0 Hz, 1H), 6.94 (td, J = 73.1, 1.1 Hz, 1H), 5.08(d, J = 10.5 Hz, 1H), 4.36 (dd, J = 10.5, 8.0 Hz, 1H), 2.83 (p, J = 7.6Hz, 1H), 1.73 -1.65 (m, 3H), 0.87 (dq, J = 7.4, 2.3 Hz, 3H) ppm. 15rel-(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(second eluting isomer by SFC) ESI-MS m/z found 527.1 (M+1)⁺; Retentiontime: 3.23 minutes ¹H NMR (500 MHz, Methanol-d₄) δ 7.97 (dd, J = 6.5,2.8 Hz, 1H), 7.78 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.37 - 7.24 (m, 2H),7.20 (dd, J = 10.5, 9.0 Hz, 1H), 6.95 (td, J = 73.1, 1.0 Hz, 1H), 5.09(d, J = 10.5 Hz, 1H), 4.37 (dd, J = 10.5, 8.0 Hz, 1H), 2.84 (p, J = 7.7Hz, 1H), 1.69 (d, J = 1.2 Hz, 3H), 0.88 (dt, J = 7.4, 2.4 Hz, 3H) ppm.

The following compounds were made using a method similar to thatdescribed in Example 4, except that 3-aminobenzamide was used in placeof methyl 4-aminopyridine-2-carboxylate in Step 2, and Step 3 wasomitted. In step 4, purification was performed by chiral SFC using a LuxCellulose-2 column, 5 µm particle size, 25 cm × 10 mm from Phenomenex,Inc.:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 51rel-(2S,3R,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(first eluting isomer by SFC on Lux Cellulose-2 column, rt = 2.97 min)ESI-MS m/z calc. 508.1233, found 509.1 (M+1)⁺; 507.2 (M-1)⁻; Retentiontime: 3.19 minutes ¹H NMR (500 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.06 (t, J= 1.9 Hz, 1H), 7.93 (s, 1H), 7.77 -7.74 (m, 1H), 7.58 (dt, J = 7.8, 1.3Hz, 1H), 7.51 -7.41 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.34 - 7.32 (m,2H), 7.29 (t, J = 72.2 Hz, 1H), 5.12 (d, J = 10.4 Hz, 1H), 4.28 (dd, J =10.4, 7.6 Hz, 1H), 2.76 (p, J = 7.3 Hz, 1H), 1.60 (s, 3H), 0.76 (d, J =6.4 Hz, 3H) ppm. 52rel-(2R,3S,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(second eluting isomer by SFC on Lux Cellulose-2 column, rt = 3.51 min)ESI-MS m/z calc. 508.1233, found 509.1 (M+1)⁺; 507.2 (M-1)⁻; Retentiontime: 3.18 minutes ¹H NMR (500 MHz, DMSO-d₆) δ 8.06 (t, J = 2.0 Hz, 1H),7.93 (s, 1H), 7.75 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H), 7.58 (dt, J = 7.6,1.3 Hz, 1H), 7.51 -7.46 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.35 - 7.31(m, 2H), 7.29 (t, J = 71.9 Hz, 1H), 5.12 (d, J = 10.3 Hz, 1H), 4.28 (dd,J = 10.4, 7.6 Hz, 1H), 2.76 (p, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.76 (d,J = 6.2 Hz, 3H) ppm. Amide NH not observed.

The following compound was made using a method similar to that describedin Example 4, except thatrac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid was used as the starting material for step 2.Rac-(2R,3S,4S,5R)-3-(2-(difluoromethoxy)-4-fluoro-3-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid was prepared using methods analogous to those described for otherintermediates of this application. The separation of the racemates atstep 4 was not carried out and the compound was isolated as a racemate:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 53rac-(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluoro-3-methyl-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 505.14362, found 506.1 (M+1)⁺; 504.2 (M-1)⁻; Retentiontime: 3.36 minutes ¹H NMR (500 MHz, DMSO-d₆) δ 10.70 (s, 1H), 8.49 (d, J= 5.5 Hz, 1H), 8.33 - 8.22 (m, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.82 (dd,J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.36 (dd, J = 8.8, 6.2Hz, 1H), 7.26 - 6.90 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.32 (dd, J =10.5, 7.5 Hz, 1H), 2.75 (p, J = 7.4 Hz, 1H), 2.18 (d, J = 2.0 Hz, 3H),1.60 (s, 3H), 0.79 - 0.70 (m, 3H) ppm.

The following compounds were made by separating 53 by chiral SFC (Exampe4, Step 4) using a Chiralpak AS-H column, 5 µm particle size, 25 cm × 10mm from Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 16rel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-3-methyl-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(first eluting isomer by SFC) ESI-MS m/z found 506 (M+1)⁺; Retentiontime: 3.34 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.46(d, J = 5.5 Hz, 1H), 8.10 (dd, J = 5.6, 2.3 Hz, 1H), 7.94 (d, J = 2.1Hz, 1H), 7.83 (s, 1H), 7.31 (dd, J = 8.8, 6.1 Hz, 1H), 7.06 (t, J = 8.7Hz, 1H), 5.56 (s, 1H), 4.97 (d, J = 11.1 Hz, 1H), 4.18 (dd, J = 11.1,8.0 Hz, 1H), 2.79 (p, J = 7.7 Hz, 1H), 2.25 (d, J = 2.2 Hz, 3H), 1.69(d, J = 1.1 Hz, 3H), 0.86 - 0.79 (m, 3H) ppm. 17rel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluoro-3-methyl-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(second eluting isomer by SFC) ESI-MS m/z found 507 (M+1)⁺; Retentiontime: 3.34 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.46(d, J = 5.5 Hz, 1H), 8.09 (dd, J = 5.5, 2.3 Hz, 1H), 7.93 (d, J = 2.2Hz, 1H), 7.83 (s, 1H), 7.34 - 7.29 (m, 1H), 5.54 (s, 1H), 4.96 (d, J =11.1 Hz, 1H), 4.18 (dd, J = 11.2, 8.1 Hz, 1H), 2.78 (p, J = 7.7 Hz, 1H),2.24 (d, J = 2.2 Hz, 3H), 1.69 (d, J = 1.1 Hz, 3H), 0.86 -0.76 (m, 3H)ppm.

Example 5(2r.3s,4s,5r)-4-[[3-[2-(Difluoromethoxy)-3,4-Difluoro-Phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]-1-Oxido-Pyridin-1-Ium-2-Carboxamide(18)

To a solution of(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(11, 35 mg, 0.06802 mmol) in DCM (1 mL) was added m-CPBA (50 mg, 0.2028mmol) in one portion at ambient temperature. After 16 hours a furtherportion of m-CPBA (50 mg, 0.2028 mmol) was added and thereaction stirredfor 4 days. The mixture was concentrated in vacuo and the remainingsolid purified by silica gel chromatography (4 g, 0 to 100% EA inheptane) to afford(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamide(18, 33 mg, 90%). ¹H NMR (500 MHz, Methanol-d₄) δ 8.47 (d, J = 3.2 Hz,1H), 8.18 (d, J = 7.3 Hz, 1H), 7.93 (dd, J = 7.3, 3.2 Hz, 1H), 7.23-7.12 (m, 2H), 6.83 (td, J = 73.1, 1.1 Hz, 1H), 5.00 (d, J = 10.4 Hz,1H), 4.26 (dd, J = 10.5, 8.1 Hz, 1H), 2.72 (p, J = 7.6 Hz, 1H), 1.56 (s,3H), 0.75 (dq, J = 4.7, 2.4 Hz, 3H) ppm. ESI-MS m/z calc. 525.11346,found 526.6 (M+1)⁺; 524.7 (M-1)⁻.

The following compounds were made using a method similar to Example 5,using 5, 7, 9, 26, and 27, respectively, as the starting materials:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 19(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamideESI-MS m/z found 490.5 (M+1)⁺; Retention time: 3.014 minutes ¹H NMR (500MHz, DMSO-d₆) δ 10.79 (s, 1H), 10.58 (d, J = 4.6 Hz, 1H), 8.52 (d, J =3.3 Hz, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 4.7 Hz, 1H), 7.87(dd, J = 7.2, 3.3 Hz, 1H), 7.16 (dd, J = 9.7, 6.5 Hz, 2H), 5.08 (d, J =10.2 Hz, 1H), 4.24 (dd, J = 10.2, 7.7 Hz, 1H), 3.94 (d, J = 2.1 Hz, 3H),2.76 (p, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.72 (dd, J = 7.6, 2.3 Hz, 3H)ppm. 54rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamideESI-MS m/z calc. 475.11667, found 476.1 (M+1)⁺; 474.0 (M-1)⁻; Retentiontime: 2.82 minutes ¹H NMR (500 MHz, Chloroform-d) δ 11.10 (d, J = 5.2Hz, 1H), 8.84 (s, 1H), 8.29 (dd, J = 7.2, 3.3 Hz, 1H), 8.25 - 8.14 (m,2H), 6.99 (ddd, J = 8.0, 5.6, 1.9 Hz, 1H), 6.94 -6.86 (m, 1H), 6.15 (s,1H), 4.77 (d, J = 10.7 Hz, 1H), 3.99 (d, J = 2.6 Hz, 3H), 3.88 - 3.76(m, 1H), 2.61 (t, J = 12.5 Hz, 1H), 2.34 (dd, J = 13.1, 8.2 Hz, 1H),1.65 (s, 3H) ppm. 55(2R,3S,4S,5R)-4-[[3-(2-ethoxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamideESI-MS m/z calc. 503.14795, found 504.5 (M+1)⁺; 502.5 (M-1)⁻; Retentiontime: 3.17 minutes ¹H NMR (500 MHz, DMSO-d₆) δ 10.82 (s, 1H), 10.59 (d,J = 4.7 Hz, 1H), 8.53 (d, J = 3.2 Hz, 1H), 8.32 (d, J = 7.2 Hz, 1H),8.22 (d, J = 4.6 Hz, 1H), 7.88 (dd, J = 7.2, 3.2 Hz, 1H), 7.22 - 7.09(m, 2H), 5.09 (d, J = 10.4 Hz, 1H), 4.28 (dd, J = 10.5, 7.6 Hz, 1H),4.25 - 4.11 (m, 2H), 2.75 (p, J = 7.4 Hz, 1H), 1.61 (s, 3H), 1.35 (t, J= 7.0 Hz, 3H), 0.73 (d, J = 7.1 Hz, 3H) ppm. 564-[[(2R,3S,4S,5R)-3-[3,4-difluoro-2-(trideuteriomethoxy)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamideESI-MS m/z calc. 492.15115, found 493.6 (M+1)⁺; 491.6 (M-1)⁻; Retentiontime: 3.02 minutes 574-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-1-oxido-pyridin-1-ium-2-carboxamideESI-MS m/z calc. 475.11667, found 476.6 (M+1)⁺; 474.4 (M-1)⁻; Retentiontime: 2.35 minutes ¹H NMR (500 MHz, Methanol-d₄) δ 8.58 (d, J = 3.2 Hz,1H), 8.30 (d, J = 7.2 Hz, 1H), 8.07 (dd, J = 7.2, 3.2 Hz, 1H), 7.03(ddd, J = 8.4, 5.7, 2.1 Hz, 1H), 6.72 (ddd, J = 10.1, 8.8, 7.4 Hz, 1H),5.12 (d, J = 10.4 Hz, 1H), 4.34 (dd, J = 10.5, 7.8 Hz, 2H), 2.92 (p, J =7.6 Hz, 1H), 1.68 (s, 2H), 0.83 (dt, J = 7.5, 2.3 Hz, 3H) ppm; Amide NHand NH₂; alcohol OH not observed.

Compound 19 - Solid Form A

A crystalline form of Compound 19, referred to herein as Form A, wasobtained from a suspension of Compound 19 in ethanol, acetonitrile, andwater by lyophilization. Form A can also be obtained by precipitationfrom a methanol solution via addition of heptane antisolvent. Form A wascharacterized by XRPD, solid state NMR (¹³C and ¹⁹F), and single-crystalX-ray analysis.

The XRPD pattern of Form A is depicted in FIG. 15 , and thecorresponding data are summarized in the following table:

Angle (° 2θ ± 0.2) Rel. Intensity (%) 6.8 8.8 13.7 100 14.3 11.1 15.224.1 16.1 12.2 18.2 51.5 18.3 23.5 19.1 10.0 20.6 10.4 20.8 22.0 22.511.6 23.8 13.6 24.0 7.5 25.8 11.8 26.3 7.9 26.6 7.7

The solid state ¹³C NMR spectrum of Form A is depicted in FIG. 16 , andthe corresponding data are summarized in the following table:

Chemical Shift [ppm] Rel. Intensity (%) 171.4 39.1 164.2 29.2 151.8 6.3149.5 8.2 148.4 44.8 146.6 4.3 144.0 5.4 141.6 86.1 138.7 35.3 126.262.8 123.8 59.1 118.0 100.0 112.2 49.2 86.4 19.1 78.8 67.1 63.3 65.247.6 71.9 43.8 50.2 23.0 56.9 11.6 58.6

The solid state ¹⁹F NMR spectrum of Form A is depicted in FIG. 17 , andthe corresponding data are summarized in the following table:

Chemical Shift [ppm] Rel. Intensity -74.6 2.4 -141.5 12.5 -154.6 8.4

The absolute stereochemistry of Compound 19 was confirmed by singlecrystal X-ray crystallographic analysis. Crystals having Form A weregrown for single-crystal X-ray analysis by dissolving ~1 mg of Compound19 material in 150 µL of methanol and allowing slow diffusion of heptaneantisolvent over several days. The thermal ellipsoid plot, at 50%probability, is depicted in FIG. 18 , and the unit cell parameters arereported in the following table:

Crystal System: Monoclinic Space Group: P2₁ a (Å) 11.2266(3) b (Å)7.3948(2) c (Å) 13.1432(4) α (°) 90 β (°) 100.3980(10) γ (°) 90 V (Å³)1073.21(5) Z/Z′ 2/0.5 Temperature 173(2)K

Example 6Rel-(2s,3r,5s)-4-[[3-(3-Chloro-4-Fluoro-2-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(20),(2s,3r,5r)-4-[[3-(3-Chloro-4-Fluoro-2-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(21),Rel-(2r,3s,5r)-4-[[3-(3-Chloro-4-Fluoro-2-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(22), and(2r,3s,5s)-4-[[3-(3-Chloro-4-Fluoro-2-MethoxyPhenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(23)

Step 1

Trifluoromethylsulfonyl trifluoromethanesulfonate (1.53 g, 5.42 mmol)was added dropwise to a solution of ethyl5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1000mg, 4.16 mmol) and triethylamine (1.26 g, 12.45 mmol) in DCM (40 mL)stirring at -78° C. After 2 h, the reaction was quenched by addition ofsaturated aqueous NaHCO₃ solution, the layers were separated and theaqueous layer extracted with DCM. The combined organic layers werepassed through a phase separator cartridge, filtered and concentrated invacuo to give ethyl2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(2.7 g, 87% yield) at 50% purity (containing 1 eq. NEt₃), which was usedwithout further purification. ESI-MS m/z calc. 372.01022, found 373.0(M+1)⁺.

Step 2

A mixture of ethyl2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(2 g, 50% purity with 1 eq. NEt₃, 2.686 mmol),2-(3-chloro-4-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(925.8 mg, 3.231 mmol) and Pd(PPh₃)₂Cl₂ (97.63 mg, 0.14 mmol) in dioxane(25 mL) and saturated aqueous NaHCO₃ (excess) was degassed, refilledwith N₂ (three times before catalyst addition, then three times aftercatalyst addition), and heated at 80° C. for 4 hours. The reactionmixture was cooled to ambient temperature and filtered through a celitecartridge, eluting with EtOAc, then the filtrate concentrated in vacuo.Purification by flash chromatography (40 g SiO₂ 0 to 20% EtOAc inheptane) gave ethyl4-(3-chloro-4-fluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(800 mg, 78%) as a clear oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.12 (dd,J = 8.7, 6.1 Hz, 1H), 6.96 (t, J = 8.5 Hz, 1H), 4.19 (q, J = 7.1 Hz,2H), 3.80 (s, 3H), 3.52 (d, J = 17.6 Hz, 1H), 2.96 (dt, J = 17.6, 0.9Hz, 1H), 1.69 (d, J = 1.0 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H) ppm. ESI-MSm/z calc. 382.0595, found 383.3 (M+1)⁺.

Step 3

A pressure tube was loaded with magnesium powder (770 mg, 31.68 mmol)and purged with nitrogen. To the reaction vessel was added MeOH (12 mL)followed by a solution of ethyl4-(3-chloro-4-fluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(600 mg, 1.57 mmol) in MeOH (12 mL) and the resulting solution wasdegassed with nitrogen. A few drops of 1,2-dibromoethane (12 µL, 0.14mmol) were added and the reaction mixture was stirred vigorously at 50°C. After 5 hours the reaction mixture was cooled and quenched by pouringslowly onto a cooled 1 M solution of HCl. The mixture was stirred for 30mins until clear. TBME was added to solution while stirring, the layersseparated and the aqueous layer extracted with TBME (x 3). The combinedorganic layers were passed through a phase separator cartridge and thefiltrate concentrated in vacuo to give ethyl3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(550 mg, 91%), which was used without further purification. ESI-MS m/zcalc. 384.07516, found 385.2 (M+1)⁺.

Step 4

Ethyl3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(550 mg, 1.43 mmol) was dissolved in ethanol (25 mL) and LiOH (5 mL of 2M, 10.00 mmol) was added. The resulting white suspension was stirred atambient temperature overnight before being concentrated in vacuo andthen partitioned between EtOAc and 1 M aqueous HCl. The layers wereseparated and the organic layer passed through a phase separatorcartridge). The filtrate was concentrated in vacuo to give a yellow oilwhich was dissolved in tert-butanol (20 mL). Potassium tert-butoxide(800 mg, 7.129 mmol) was added and the mixture stirred at ambienttemperature overnight. The reaction mixture was evaporated in vacuo togive potassium3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(500 mg, 88%). ESI-MS m/z calc. 356.04385, found 355.2 (M-1)⁻.

Step 5

To a solution of potassium3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(500 mg, 1.40 mmol) in DCM (20 mL) stirring at ambient temperature wasadded DMF (25 µL, 0.32 mmol) and oxalyl chloride (415 µL, 4.76 mmol).After 15 mins the reaction mixture was concentrated in vacuo then theresidue diluted in DCM (10 mL) and added dropwise over 5 mins to asolution of methyl 4-aminopyridine-2-carboxylate (334 mg, 2.20 mmol),DMAP (16.55 mg, 0.14 mmol) and Et₃N (1.2 mL, 8.61 mmol) in DCM (10 mL)stirring at 0° C. After 10 mins the reaction was warmed to ambienttemperature and after 40 mins the reaction mixture was diluted with DCM(50 mL) and washed with 2 M HCl solution (50 mL). The organic layer waspassed through a phase separator cartridge and the filtrate wasconcentrated in vacuo to give methyl4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(670 mg, 97%), which was used without further purification. ESI-MS m/zcalc. 490.09186, found 491.1 (M+1)⁺.

Step 6

Methyl4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(470 mg, 0.96 mmol) was dissolved in methanolic ammonia (10.00 mL of 2M, 20.00 mmol) and stirred overnight at ambient temperature. Thereaction mixture was evaporated in vacuo to give4-[[3-(3-chloro-4-fluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(420 mg, 92%), which was used without further purification. ESI-MS m/zcalc. 475.0922, found 476.4 (M+1)⁺.

Step 7

(4-[[3-(3-Chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(420 mg, 0.8827 mmol) was separated by chiral SFC [(R,R)-Whelk-O1column, 5 µm particle size, 25 cm × 21.2 mm from Regis Technologies,MeOH, 20 mM NH₃], followed by further purification of one or more of thefractions by chiral SFC using a Chiralpak IC column, 5 µm particle size,25 cm × 20 mm from Daicel or a Chiralpak ID column, 5 µum particle size,25 cm x 20 mm from Daicel to give:

First Eluting Isomer:rel-(2S,3R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(20, 30 mg, 7.1%) (further purified by chiral SFC using Chiralpak ICcolumn). ¹H NMR (500 MHz, Chloroform-d) δ 8.92 (s, 1H), 8.47 (d, J = 5.5Hz, 1H), 8.21 (dd, J = 5.6, 2.1 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.87(d, J = 4.1 Hz, 1H), 7.26 (dd, J = 8.8, 5.8 Hz, 1H), 7.03 (t, J = 8.4Hz, 1H), 5.87 - 5.82 (m, 1H), 4.77 (d, J = 10.6 Hz, 1H), 3.98 (td, J =11.2, 8.3 Hz, 1H), 3.88 (s, 3H), 2.51 (dd, J = 13.2, 11.7 Hz, 1H), 2.42(dd, J = 13.2, 8.3 Hz, 1H), 1.69 (s, 3H) ppm. ESI-MS m/z calc. 475.0922,found 476.4 (M+1)⁺; 474.4 (M-1)⁻.

Second Eluting Isomer:(2S,3R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(21, 29 mg, 6.7%) (further purified by chiral SFC using Chiralpak IDcolumn). ¹H NMR (500 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.48 (d, J = 5.5Hz, 1H), 8.08 (dd, J = 5.5, 2.2 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.86(d, J = 4.4 Hz, 1H), 7.23 (dd, J = 8.8, 5.8 Hz, 1H), 7.01 (t, J = 8.4Hz, 1H), 5.86 (d, J = 4.2 Hz, 1H), 4.80 (d, J = 9.7 Hz, 1H), 4.10 - 4.00(m, 1H), 3.93 (s, 3H), 3.52 - 3.48 (m, 1H), 2.86 (dd, J = 13.9, 8.4 Hz,1H), 2.16 -2.07 (m, 1H), 1.64 (s, 2H) ppm. ESI-MS m/z calc. 475.0922,found 476.4 (M+1)⁺; 474.4 (M-1)⁻.

Third Eluting Isomer:rel-(2R,3S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(22, 42 mg, 9.5%). ¹H NMR (500 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.33(d, J = 5.6 Hz, 1H), 8.08 (dd, J = 5.6, 2.2 Hz, 1H), 7.98 (d, J = 2.2Hz, 1H), 7.74 (d, J = 4.5 Hz, 1H), 7.12 (dd, J = 8.8, 5.8 Hz, 1H), 6.89(t, J = 8.4 Hz, 1H), 5.79 (d, J = 4.5 Hz, 1H), 4.63 (d, J = 10.7 Hz,1H), 3.85 (td, J = 11.2, 8.4 Hz, 1H), 3.74 (s, 3H), 2.37 (dd, J = 13.2,11.7 Hz, 1H), 2.28 (dd, J = 13.1, 8.4 Hz, 1H), 1.55 (s, 3H) ppm. ESI-MSm/z calc. 475.0922, found 476.4 (M+1)⁺; 474.4 (M-1)⁻.

Fourth Eluting Isomer:(2R,3S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(23, 40 mg, 8.8%). ¹H NMR (500 MHz, Chloroform-d) δ 8.43 (s, 1H), 8.35(d, J = 5.5 Hz, 1H), 7.95 (dd, J = 5.5, 2.2 Hz, 1H), 7.85 (d, J = 2.2Hz, 1H), 7.73 (d, J = 4.3 Hz, 1H), 7.10 (dd, J = 8.8, 5.9 Hz, 1H), 6.87(t, J = 8.4 Hz, 1H), 5.76 - 5.71 (m, 1H), 4.67 (d, J = 9.7 Hz, 1H),3.97 - 3.87 (m, 1H), 3.80 (s, 3H), 2.73 (dd, J = 13.9, 8.4 Hz, 1H), 1.98(dd, J = 13.9, 11.6 Hz, 1H), 1.51 (s, 3H) ppm. ESI-MS m/z calc.475.0922, found 476.4 (M+1)⁺; 474.4 (M-1)⁻.

Compound 22 - Solid Form A

A crystalline form of Compound 22, referred to herein as Form A, wasgenerated by slow evaporation of a 1:1 2-methyltetrahydrofuran/heptanesolution. Form A was characterized by XRPD and solid state NMR (¹³C and¹⁹F) analysis.

The XRPD pattern of Form A is depicted in FIG. 19 , and thecorresponding data are summarized in the following table:

Angle (° 2θ 0.2) Rel. Intensity (%) 7.7 48.9 9.2 95.9 10.4 100 12.9 44.813.8 9.9 14.7 13.4 15.7 46.2 16.1 27.4 18.4 46.0 19.8 26.5 21.7 23.622.3 13.6 24.0 23.8

The solid state ¹³C NMR spectrum of Form A is depicted in FIG. 20 , andthe corresponding data are summarized in the following table:

Chemical Shift [ppm] Rel. Intensity (%) 172.6 41.8 167.7 56.7 158.7 14.5156.8 34.9 151.8 43.8 148.7 65.9 128.6 44.0 126.0 62.1 115.9 77.5 113.154.9 112.3 58.0 88.0 60.7 85.5 64.1 62.0 40.7 60.5 52.3 55.6 21.3 43.5100.0 37.7 22.1 29.6 11.0 21.1 57.3 20.3 62.9

The solid state ¹⁹F NMR spectrum of Form A is depicted in FIG. 21 , andthe corresponding data are summarized in the following table:

Chemical Shift [ppm] Rel. Intensity -82.2 11.7 -83.1 12.5 -111.7 1.8-114.4 3.0

Compound 23 - Solid Form A

A crystalline form of Compound 23, referred to herein as Form A, wasgenerated by slow evaporation of a 1:1 2-methyltetrahydrofuran/heptanesolution. Form A was characterized by XRPD, solid state NMR (¹³C and¹⁹F), and single-crystal X-ray analysis.

The XRPD pattern of Form A is depicted in FIG. 22 , and thecorresponding data are summarized in the following table:

Angle (° 2θ ± 0.2) Rel. Intensity (%) 11.3 5.8 12.2 16.8 13.2 6.9 14.222.2 15.2 13.1 15.8 25.5 16.6 10.2 17.2 100 19.3 71.7 21.1 14.4 22.337.3 22.8 24.9 23.7 7.0 24.6 8.7 25.0 16.7 25.1 19.7 25.9 10.9 27.1 5.327.9 13.2 30.6 31.6 34.4 6.7 39.4 11.5

The solid state ¹³C NMR spectrum of Form A is depicted in FIG. 23 , andthe corresponding data are summarized in the following table:

Chemical Shift [ppm] Rel. Intensity (%) 171.1 60.6 166.7 59.9 156.8 19.4155.5 27.1 151.9 64.5 149.3 83.3 147.3 56.5 131.5 42.1 123.3 56.1 119.049.1 114.2 76.6 112.8 54.0 86.0 98.6 85.0 39.0 61.7 36.4 61.0 54.8 44.453.9 41.6 88.6 20.0 100.0

The solid state ¹⁹F NMR spectrum of Form A is depicted in FIG. 24 , andthe corresponding data are summarized in the following table:

Chemical Shift [ppm] Rel. Intensity -78.2 12.5 -113.5 3.7 -115.1 4.7

Crystals having Form A were grown for single-crystal X-ray analysis bydissolving ~1 mg of Compound 23 material in 150 µL of methanol andallowing diffusion of heptane vapor over several days. The thermalellipsoid plot, at 50% probability, is depicted in FIG. 25 , and theunit cell parameters are reported in the following table:

Crystal System: Monoclinic Space Group: P2₁ a (Å) 7.8661(3) b (Å)7.9167(3) c (Å) 16.8777(7) α (°) 90 β (°) 98.487(2) γ (°) 90 V (Å³)1039.52(7) Z 2 Temperature 173(2)K

The following compounds were made using a method similar to thatdescribed in Example 6, except that methylamine was used in place ofammonia in Step 7. In step 4, purification was performed by chiral SFCusing a (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x 21.2 mm fromRegis Technologies on a Minigram SFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 58rel-(2S,3R,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methylpyridine-2-carboxamide(first eluting isomer by SFC on Whelk01 column, rt = 3.41 min) ESI-MSm/z calc. 489.10785, found 490.4 (M+1)⁺; 488.4 (M-1)⁻; Retention time:3.21 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.46 (d, J =5.5 Hz, 1H), 8.18 (dd, J = 5.6, 2.2 Hz, 1H), 8.13 (s, 1H), 7.93 (d, J =2.2 Hz, 1H), 7.25 (dd, J = 8.8, 5.8 Hz, 1H), 7.07 - 6.95 (m, 1H), 4.75(d, J = 10.7 Hz, 1H), 3.99 - 3.85 (m, 1H), 3.89 (s, 3H), 3.06 (d, J =5.0 Hz, 3H), 2.51 (dd, J = 13.2, 11.7 Hz, 1H), 2.42 (dd, J = 13.2, 8.3Hz, 1H), 1.68 (s, 3H) ppm. 59rel-(2R,3S,5S)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (second elutingisomer by SFC on Whelk01 column, rt = 3.81 min) ESI-MS m/z calc.489.10785, found 490.4 (M+1)⁺; 488.4 (M-1)⁻; Retention time: 3.17minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.48 (s, 1H), 8.36 (d, J = 5.5Hz, 1H), 8.08 - 8.00 (m, 2H), 7.86 (d, J = 2.2 Hz, 1H), 7.14 (dd, J =8.8, 5.9 Hz, 1H), 6.92 (dd, J = 8.8, 8.1 Hz, 1H), 4.71 (d, J = 9.7 Hz,1H), 4.01 - 3.91 (m, 1H), 3.84 (s, 3H), 2.97 (d, J = 5.1 Hz, 3H), 2.77(dd, J = 13.9, 8.4 Hz, 1H), 2.03 (dd, J = 13.8, 11.7 Hz, 1H), 1.56 (s,2H) ppm. 60rel-(2R,3S,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (third elutingisomer by SFC on Whelk01 column, rt = 4.32 min) ESI-MS m/z calc.489.10785, found 490.4 (M+1)⁺; 488.4 (M-1)⁻; Retention time: 3.22minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.54 (s, 1H), 8.36 (d, J = 5.5Hz, 1H), 8.09 (dd, J = 5.6, 2.2 Hz, 1H), 8.05 (s, 1H), 7.84 (d, J = 2.1Hz, 1H), 7.16 (dd, J = 8.8, 5.9 Hz, 1H), 6.93 (t, J = 8.4 Hz, 1H), 4.66(d, J = 10.7 Hz, 1H), 3.85 (td, J = 11.3, 8.4 Hz, 1H), 3.79 (s, 3H),2.97 (d, J = 5.0 Hz, 3H), 2.41 (dd, J = 13.2, 11.7 Hz, 1H), 2.32 (dd, J= 13.2, 8.4 Hz, 1H), 1.59 (s, 3H) ppm. 61rel-(2S,3R,5R)-4-[[3-(3-chloro-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-N-methyl-pyridine-2-carboxamide (fourth elutingisomer by SFC on Whelk01 column, rt = 4.93 min) ESI-MS m/z calc.489.10785, found 490.4 (M+1)⁺; 488.4 (M-1)⁻; Retention time: 3.16minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.45 (d, J = 5.6Hz, 1H), 8.12 (dd, J = 5.6, 2.2 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.23(dd, J = 8.8, 5.8 Hz, 1H), 7.01 (dd, J = 8.7, 8.1 Hz, 1H), 4.80 (d, J =9.7 Hz, 1H), 4.11 - 4.01 (m, 1H), 3.93 (s, 3H), 3.06 (d, J = 5.0 Hz,3H), 2.91 - 2.82 (m, 1H), 2.16 - 2.07 (m, 1H), 1.64 (d, J = 1.1 Hz, 3H)ppm.

Example 7Rel-(2r,3s,4s,5r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(24) andRel-(2s,3r,4r,5s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(25)

Step 1

A solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (25 g of 50%w/w, 99.57 mmol) and potassium carbonate (21.5 g, 155.6 mmol) in water(40 mL) were added to a solution of methyl 4-bromofuran-2-carboxylate(10 g, 48.78 mmol) in 2-methyltetrahydrofuran (200 mL) and the reactionmixture degassed for 10 mins. Pd(amphos)Cl₂ (1.5 g, 2.12 mmol) was addedand the reaction mixture further degassed for 5 mins before the reactionwas heated at 60° C. for 4 hours. The reaction was then cooled toambient temperature, filtered through a small pad of celite and washedwith MTBE (200 mL). The layers were separated and the aqueous layerextracted with MTBE (2 × 20 mL). The combined organic extracts weredried (Na₂SO₄) and carefully concentrated in vacuo (approximately 90mBar, no heating) to give methyl 4-methylfuran-2-carboxylate (6.836 g,100%) which was used without any further purification.

Step 2

To a solution of methyl 4-methylfuran-2-carboxylate (10 g, 48.78 mmol)in THF (40 mL), water (40 mL) and MeOH (10 mL) stirring at ambienttemperature was added LiOH·H₂O (12.3 g, 293.11 mmol). The reaction wasstirred for 2 hours before MTBE (100 mL) and water (100 mL) were added.The aqueous layer was isolated and treated with 6 N HCl solution toadjust the pH to about 3-4, then extracted with MTBE (2 × 50 mL). Thecombined organic layers were concentrated in vacuo to afford4-methylfuran-2-carboxylic acid (5.5 g, 89%) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 12.92 (s, 1H), 7.65 (s, 1H), 7.07 (s, 1H), 2.00(s, 3H) ppm.

Step 3

To a solution of 4-methylfuran-2-carboxylic acid (150 mg, 1.19 mmol) inDCE (25 mL) was added tris(2, 2′-bipyridyl)dichlororuthenium(II)hexahydrate (17 mg, 0.023 mmol) and pyridine (288 µL, 3.56 mmol) thentriflic anhydride (599 µL, 3.56 mmol) dropwise over 5 mins. The mixturewas irradiated with blue LEDs for 2 hours at ambient temperaturestirring at 800 rpm, using a PennPhD Photoreacter m2 (using 450 nm blueLED lights) and an EvoluChem™ PhotoRedOx Box device (using 455 nm blueLED lights) used in parallel. This process was repeated in 5 batches andthe crude material combined for purification. The combined reactionmixtures were washed with 1 M NaCO₃ (2 × 80 mL) and the organic layerdiscarded. The combined aqueous layers were acidified to pH 2 using 1 MHCl and extracted with MTBE (2 × 50 mL). The combined organic layerswere washed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo.The residue was redissolved in a small amount of diethyl ether andslowly triturated by addition of petroleum ether and allowed to stir.The liquid was decanted to afford4-methyl-5-(trifluoromethyl)furan-2-carboxylic acid (700 mg at 90%purity, 55%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.75(brs, 1H), 7.29 (d, J = 1.2 Hz, 1H), 2.19 (q, J = 2.0 Hz, 3H) ppm.ESI-MS m/z calc. 194.01907, found 193.3 (M-1)⁻.

Step 4

To a solution of 4-methyl-5-(trifluoromethyl)furan-2-carboxylic acid(2.8 g, 14.03 mmol) in THF (40 mL) stirring at -78° C. was added n-BuLi(14 mL of 2.5 M in hexanes, 35.00 mmol). The solution was stirred at-78° C. for 20 mins before a solution of iodine (3.9 g, 15.37 mmol) inTHF (5 mL) was added. The mixture was allowed to warm to ambienttemperature, then partitioned between MTBE (80 mL) and water (100 mL).The organic layer was discarded and the aqueous layer acidified to pH 2with 1 M HCl and extracted with MTBE (2 × 40 mL). The combined organicfractions were washed with brine (20 mL), dried (MgSO₄) and concentratedin vacuo. Purification by flash chromatography (40 g SiO₂, 0 to 100%MTBE in petroleum ether) gave3-iodo-4-methyl-5-(trifluoromethyl)furan-2-carboxylic acid (3.1 g, 69%)as an oil. ESI-MS m/z calc. 319.9157, found 319.3 (M-1)⁻.

Step 5

To a solution of 3-iodo-4-methyl-5-(trifluoromethyl)furan-2-carboxylicacid (300 mg at 71% purity, 0.6656 mmol) in DMF (5 mL) was addedpotassium carbonate (276 mg, 2.00 mmol) and iodoethane (160 µL, 2.00mmol). The mixture was heated at 50° C. for 2 hours then cooled toambient temperature and partitioned between MTBE (40 mL) and water (80mL). The layers were separated and the aqueous layer further extractedwith MTBE (30 mL). The combined organic fractions were washed with brine(1 × 20 mL), dried (MgSO₄) and concentrated in vacuo. Purification byflash chromatography (80 g SiO₂, 0 to 100% EtOAc in petroleum ether)gave ethyl 3-iodo-4-methyl-5-(trifluoromethyl)furan-2-carboxylate (220mg at 80% purity, 76%) as an oil. ¹H NMR (500 MHz, Chloroform-d) δ 4.42(dq, J = 20.1, 7.1 Hz, 2H), 2.24 - 2.11 (m, 3H), 1.42 (dt, J = 20.2, 7.1Hz, 3H) ppm.

Step 6

To a solution of ethyl3-iodo-4-methyl-5-(trifluoromethyl)furan-2-carboxylate (500 mg at 71%purity, 1.01 mmol) in dioxane (2 mL) was added(3,4-difluoro-2-methoxy-phenyl)boronic acid (476 mg, 2.533 mmol),Pd(dppf)Cl₂·DCM (83 mg, 0.10 mmol) and aqueous sodium carbonate (2 mL of2 M, 4.00 mmol). The mixture was heated at 80° C. for 1 hour beforebeing cooled to ambient temperature and partitioned between MTBE (30 mL)and water (30 mL). The layers were separated and the aqueous layerfurther extracted with MTBE (10 mL). The combined organic fractions werewashed with brine (1 × 20 mL), dried (MgSO₄) and concentrated in vacuo.Purification by flash chromatography (12 g SiO₂, 0 to 100% EtOAc inpetroleum ether) gave ethyl3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)furan-2-carboxylate(330 mg at 80% purity, 71%) as an oil. ESI-MS m/z calc. 364.0734, found365.4 (M+1)⁺.

Step 7

A solution of ethyl3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)furan-2-carboxylate(410 mg at 70% purity, 0.7879 mmol) in ethanol (2 mL) was passed througha 70 mm palladium hydroxide (90.52 mg, 0.64 mmol) CatCart® on an H-Cube®at 60° C. and 60 bar pressure of hydrogen. The mixture was recirculatedfor 30 hours before being concentrated in vacuo to give ethylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(300 mg at 75% purity, 58%), which was used in the next step withoutfurther purification. ESI-MS m/z calc. 368.1047, found 369.3 (M+1)⁺.

Step 8

To a solution of ethylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(900 mg at 80% purity, 2.44 mmol) in THF (5 mL) stirring at 0° C. wasadded KOt-Bu (822 mg, 7.33 mmol). The reaction was stirred for 30 minsbefore being diluted with MTBE (5 mL) and quenched by addition of 1 MHCl. The layers were separated and the aqueous layer was furtherextracted with MTBE (5 mL). The combined organic layers were dried(MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (500 mg at 52% purity, 31%) as an oil, which was used withoutfurther purification. ESI-MS m/z calc. 340.0734, found 339.4 (M-1)⁻.

Step 9

To an ice-cooled solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (380 mg at 52% purity, 0.58 mmol) in 2-methyltetrahydrofuran (5 mL)was added a solution of DMF (5 mg, 0.068 mmol) in2-methyltetrahydrofuran and oxalyl chloride (116 µL, 1.330 mmol)dropwise. The mixture was warmed to ambient temperature over 30 minsthen concentrated in vacuo. The residue was redissolved in2-methyltetrahydrofuran (5 mL) and methyl 4-aminopyridine-2-carboxylate(114 mg, 0.75 mmol) and NEt₃ (162 µL, 1.16 mmol) were added. The mixturewas warmed to ambient temperature over 1 hour before being quenched bythe addition of water (10 mL). The layers were separated and the aqueouslayer extracted with EtOAc (2 × 10 mL). The combined organic layers weredried (MgSO₄), filtered and concentrated in vacuo to give methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(210 mg at 86% purity, 65%). ESI-MS m/z calc. 474.1214, found 475.5(M+1)⁺.

Step 10 and 11

To a solution of methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(200 mg at 86% purity, 0.42 mmol) in MeOH (2 mL) was added methanolicammonia (322 µL of 7 M, 2.25 mmol). The mixture was stirred at ambienttemperature for 6 hours before being concentrated in vacuo to affordrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide.The residue was purified by chiral SFC using a Chiralpak ASH column, 5µm particle size, 25 cm x 10 mm from Daicel on a Minigram SFC instrumentfrom Berger Instruments to give:

First Eluting Isomer:rel-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(24, 60 mg). ¹H NMR (500 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.49 (d, J =5.6 Hz, 1H), 8.14 (dd, J = 5.5, 2.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H),7.85 (s, 1H), 7.10 (ddd, J = 7.9, 5.4, 2.0 Hz, 1H), 6.94 (td, J = 9.2,7.5 Hz, 1H), 5.60 (s, 1H), 5.07 (d, J = 10.7 Hz, 1H), 4.78 - 4.65 (m,1H), 4.08 - 3.94 (m, 4H), 3.09 - 2.94 (m, 1H), 0.83 (dt, J = 7.3, 2.0Hz, 3H) ppm. ESI-MS m/z calc. 459.12173, found 460.2 (M+1)⁺.

Second Eluting Isomer:rel-(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(25, 68 mg). ¹H NMR (500 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.49 (d, J =5.6 Hz, 1H), 8.14 (dd, J = 5.5, 2.2 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H),7.85 (s, 1H), 7.10 (ddd, J = 7.9, 5.4, 2.0 Hz, 1H), 6.94 (td, J = 9.2,7.5 Hz, 1H), 5.60 (s, 1H), 5.07 (d, J = 10.7 Hz, 1H), 4.78 - 4.65 (m,1H), 4.08 - 3.94 (m, 4H), 3.09 - 2.94 (m, 1H), 0.83 (dt, J = 7.3, 2.0Hz, 3H) ppm. ESI-MS m/z calc. 459.12173, found 460.2 (M+1)⁺.

Compound 25 - Solid Form A

Compound 25 was dissolved in a 1:1 mixture of 2-methyltetrahydrofuranand heptane, and the mixture was subjected to slow evaporation of thesolvent, producing a crystalline form of Compound 25, which is referredto herein as Form A. Form A was characterized by XRPD and solid stateNMR (¹³C and ¹⁹F) analysis.

The XRPD pattern of Form A is depicted in FIG. 26 , and thecorresponding data are summarized in the following table:

Angle (° 2θ ± 0.2) Rel. Intensity (%) 3.2 5.43 6.8 29.74 7.9 100 11.013.22 11.8 4.16 13.7 26.93 13.8 36.08 15.1 18 15.9 17.42 16.3 16.21 17.53.92 18.6 3.77 19.0 8.7 19.5 6.95 21.6 7.98 21.9 6.78 23.2 11.32 27.05.04 27.4 24.34 29.4 4.93 30.3 3.29

Example 8(2r,3s,4s,5r)-4-[[3-(3,4-Difluoro-2-Hydroxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(27)

To a solution of(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(7, 280 mg, 0.59 mmol) in DCM (6 mL) stirring at 0° C. was added borontribromide (830.0 µL of 1 M, 0.83 mmol). The mixture was warmed slowlyto ambient temperature and stirred for 24 hours. The mixture was thencooled to 0° C. and additional boron tribromide (400 µL of 1 M, 0.40mmol) was added. An additional portion of boron tribromide (400 µL of 1M, 0.40 mmol) was added at 0° C., after which the mixture was warmed toand stirred at ambient temperature for 16 hours. Subsequently, water andsaturated aqueous sodium bicarbonate solution were added and the mixturewas stirred for 30 mins. The aqueous layer was isolated and extractedwith DCM, and the combined organic layers were dried and concentrated invacuo. Purification by flash chromatography (12 g SiO₂, 0 to 70% EtOAcin heptane) gave(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(162 mg, 60%) (27). ESI-MS m/z calc. 459.12, found 460.7 (M+1)⁺; 458.8(M-1)⁻. ¹H NMR (500 MHz, DMSO-d₆) δ 10.73 (s, 1H), 10.46 (s, 1H), 8.50(d, J = 5.6 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.86 - 7.82 (m, 1H),7.61 (s, 1H), 7.06 - 7.00 (m, 1H), 6.89 - 6.83 (m, 1H), 5.15 - 5.08 (m,1H), 4.29 - 4.22 (m, 1H), 2.86 - 2.80 (m, 1H), 1.61 (s, 3H), 0.72 (d, J= 7.2 Hz, 3H) ppm.

The following compound was made using a method similar to that describedin Example 8, except that (2R,3S,4S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamidewas used as the starting material in place of(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 62(2R,3S,4S,5R)-4-[[3-(4-fluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 489.10785,found 490.4 (M+1)⁺; 488.4 (M-1)⁻; Retention time: 3.21 minutes ¹H NMR(500 MHz, DMSO-d₆) δ: 10.80 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.26 (d,J = 2.1 Hz, 1H), 8.07 (d, J = 2.9 Hz, 1H), 7.84 (dd, J = 2.2, 5.5 Hz,1H), 7.62 (d, J = 2.9 Hz, 1H), 7.20 (t, J = 8.5 Hz, 1H), 6.62 (m, 2H),5.10 (d, J = 10.4 Hz, 1H), 4.20 (dd, J = 7.5, 10.5 Hz, 1H), 2.83 (p, J =7.4 Hz, 1H), 1.59 (br s, 3H), 0.70 (dd, J= 2.8, 7.6 Hz, 3H) ppm.Hydroxyl (OH) proton not observed.

Example 9Rel-(25,3r,5s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-Ethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(63) andRel-(2r,3s,5r)-4-[[3-(3,4-Difluoro-2-Methoxy-phenyl)-5-Ethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(64)

Step 1

To a solution of ethyl 2-diazo-3-oxo-butanoate (12 g, 76.9 mmol) in DCM(420 mL) stirring at -65° C. was added triethylamine (8.71 g, 12 mL,86.1 mmol) and titanium tetrachloride (85 mL of 1 M, 85.0 mmol). Theresulting deep red solution was stirred at -65° C. for 1 hour. Asolution of 1,1,1-trifluoro-2-butanone (9.75 g, 10.5 mL, 77.4 mmol) andTi(Oi-Pr)₄ (23.1 g, 24 mL, 81.3 mmol) in DCM (100 mL) was added dropwiseand the resulting mixture was stirred at -65° C. for 2 hours thenallowed to warm to ambient temperature overnight. The reaction mixturewas quenched with saturated NH₄Cl solution (200 mL) and extracted withDCM (3 × 150 mL). The combined organic phases were dried over MgSO₄,filtered and concentrated in vacuo. Purification by reverse-phase flashchromatography (C18 silica, acetonitrile/water 0-70%) afforded ethyl2-diazo-5-hydroxy-3-oxo-5-(trifluoromethyl)heptanoate (11.21 g, 51%) asa yellow liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.99 (s, 1H), 4.25 (q, J =7.1 Hz, 2H), 3.28 (d, J = 15.4 Hz, 1H), 3.16 (d, J = 15.4 Hz, 1H), 1.84(dp, J = 25.7, 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.93 (td, J = 7.5,1.2 Hz, 3H) ppm; ¹⁹F NMR (376 MHz, DMSO-d₆) δ -78.78 ppm. ESI-MS m/zcalc. 282.0827, found 282.95 (M+1)⁺.

Step 2

To a stirred suspension of rhodium(II) acetate (89 mg, 0.2014 mmol) intoluene (90 mL) at 100° C. was added a solution of ethyl2-diazo-5-hydroxy-3-oxo-5-(trifluoromethyl)heptanoate (5.8 g, 20.1 mmol)in toluene (200 mL). The reaction mixture was stirred at 100° C. for 1hour before being cooled to ambient temperature and filtered through aCelite pad, washing with DCM (6 × 50 mL). The combined filtrates wereconcentrated in vacuo to afford ethyl5-ethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (5.22 g,97%, mixture of four isomers) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆)δ 4.99 (d, J = 62.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.18 - 2.98 (m,1H), 2.90 (dd, J = 19.2, 14.4 Hz, 1H), 2.03 - 1.79 (m, 2H), 1.21 (q, J =7.2 Hz, 3H), 1.05 (td, J = 7.4, 0.9 Hz, 3H), 0.97 (td, J = 7.5, 1.0 Hz,1H) ppm; ¹⁹F NMR (376 MHz, DMSO-d₆) δ -78.68, -79.35 ppm.

Step 3

To a solution of ethyl5-ethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (4.25 g,14.7 mmol) in DCM (120 mL) stirring at -65° C. was added DIPEA (5.79 g,7.8 mL, 44.8 mmol) and trifluoromethylsulfonyl trifluoromethanesulfonate(5.37 g, 3.2 mL, 19.0 mmol). The resulting orange solution was stirredat -65° C. for 3 hours before being quenched with saturated aqueousNaHCO₃ solution (80 mL) and extracted with DCM (4 × 60 mL). The combinedorganic phases were dried over MgSO₄, filtered and concentrated invacuo. The residue was dissolved in EtOAc (500 mL) and washed with 1 MHCl (5 × 100 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated to afford ethyl2-ethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(5.84 g, 98%). ¹H NMR (300 MHz, Chloroform-d) δ 4.39 (q, J = 7.2 Hz,2H), 3.29 (d, J = 17.5 Hz, 1H), 3.09 (d, J = 17.5 Hz, 1H), 2.19 - 2.01(m, 1H), 1.81 (dd, J = 14.6, 7.4 Hz, 1H), 1.39 (t, J = 7.2 Hz, 3H),1.16 - 1.03 (m, 3H) ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ -73.84,-82.96 ppm.

Step 4

Ethyl2-ethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(5.8 g, 14.3 mmol),2-(3,4-difluoro-2-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(5.78 g, 21.4 mmol), sodium carbonate (3.78 g, 35.7 mmol), toluene (45mL), MeOH (4.5 mL) and water (4.5 mL) were placed in a 120 mL glasspressure reactor. The mixture was degassed and purged with argon threetimes. Pd(PPh₃)₄ (1.24 g, 1.07 mmol) was added and the reactor wassealed and the mixture stirred at 80° C. overnight before being cooledto ambient temperature, diluted with EtOAc (50 mL) and filtered througha pad of Celite, washing with EtOAc (6 × 50 mL). Combined filtrates wereconcentrated in vacuo. Purification by flash chromatography (SiO₂, 0-5%EtOAc in hexane) gave ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2-ethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(2.7 g, 45%) as a yellow oil. Repurification of mixed fractions by flashchromatography (SiO₂, 0-10% EtOAc in hexane) gave ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2-ethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(0.9 g, 16%) as a light-yellow oil. ¹H NMR (300 MHz, Chloroform-d) δ6.97 - 6.82 (m, 2H), 4.18 (q, J = 7.1 Hz, 2H), 3.92 (d, J = 2.0 Hz, 3H),3.32 (d, J = 17.7 Hz, 1H), 3.09 (dd, J = 17.7, 1.0 Hz, 1H), 2.13 (dq, J= 14.9, 7.5 Hz, 1H), 1.82 (dq, J = 14.7, 7.4 Hz, 1H), 1.15 (dt, J =12.4, 7.4 Hz, 6H) ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ -82.50, -135.66(ddd, J = 20.2, 9.4, 6.3 Hz), -154.83 - -154.95 (m) ppm. ESI-MS m/zcalc. 380.1047, found 381.0 (M+1)⁺.

Step 5

A solution of ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2-ethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(240 mg, 0.60 mmol) in ethanol (15 mL) was hydrogenated in an H-cubeapparatus using a Pd/C catalytic cartridge at 80° C. and 50 bar, withflow rate of 0.5 ml/min. The mixture was concentrated in vacuo to affordethylrac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(185 mg, 77%, mixture of four isomers) as a white solid; ¹H NMR (300MHz, Chloroform-d) δ 7.06 - 6.71 (m, 2H), 4.95 (d, J = 9.1 Hz, 1H),4.29 - 4.15 (m, 1H), 4.09 (d, J = 2.9 Hz, 3H), 3.82 (dddd, J = 17.9,10.8, 7.1, 3.7 Hz, 2H), 2.77 (t, J = 12.5 Hz, 1H), 2.15 (dd, J = 12.4,7.3 Hz, 1H), 1.93 (dq, J = 13.8, 7.3 Hz, 2H), 1.11 (td, J = 7.6, 1.3 Hz,3H), 0.97 (t, J = 7.2 Hz, 3H) ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ-76.93, -79.92, -136.98 (ddd, J = 19.4, 9.6, 5.4 Hz), -153.95 (d, J =12.5 Hz), -154.80 (ddt, J = 19.5, 6.2, 2.9 Hz) ppm.

Step 6

To a solution of ethylrac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(100 mg, 0.25 mmol) in tert-butanol (3 mL) at ambient temperature wasadded potassium 2-methylpropan-2-olate (84 mg, 0.75 mmol). The reactionmixture was stirred for 1 hour before being quenched with saturatedaqueous NH₄Cl solution (1 mL) and extracted with EtOAc (3 × 5 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to affordrac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (93 mg, 99%, mixture of four isomers) as a yellow oil. ¹H NMR (300MHz, Chloroform-d) δ 7.02 - 6.83 (m, 2H), 4.68 (d, J = 10.8 Hz, 1H),3.98 (d, J = 2.6 Hz, 3H), 3.76 (q, J = 10.6 Hz, 1H), 2.55 - 2.33 (m,2H), 1.95 (dt, J = 14.7, 7.3 Hz, 1H), 1.79 (dq, J = 14.6, 7.4 Hz, 1H),1.12 (t, J = 7.4 Hz, 3H) ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ -77.01,-79.71, -79.93, -137.04 (ddd, J = 19.3, 9.5, 5.6 Hz), -153.72 (d, J =20.7 Hz), -153.92 (ddd, J = 19.5, 5.0, 2.6 Hz), -154.79 (d, J = 19.5 Hz)ppm. ESI-MS m/z calc. 354.089, found 353.4 (M-1)⁻.

Step 7

To a solution ofrac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (290 mg, 0.8186 mmol) in DCM (6 mL) stirring at 0° C. was added acatalytic amount of DMF (15.1 mg, 16 µL, 0.21 mmol) and oxalyl chloride(291 mg, 194 µL, 2.29 mmol). The mixture was stirred at 0° C. for 2hours then concentrated in vacuo and azeotroped with DCM (3 × 5 mL). Theresidue was taken up in DCM (6 mL) and the resulting solution added toice-cooled solution of methyl 4-aminopyridine-2-carboxylate (137 mg,0.9004 mmol) and DIPEA (445.20 mg, 0.6 mL, 3.4447 mmol) in DCM (6 mL).The resulting mixture was stirred at 0° C. for 1 hour and then 60 hoursat ambient temperature. The mixture was poured into water (10 mL) andextracted with DCM (3 × 10 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated. Purification using flashchromatography (SiO₂, 0 to 60% EtOAc in hexane) gave methylrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(223 mg, 56%, mixture of four isomers) as a white foam. ¹H NMR (300 MHz,Chloroform-d) δ 8.65 (d, J = 5.5 Hz, 1H), 8.53 (s, 1H), 8.10 - 8.06 (m,1H), 7.96 (dd, J = 5.5, 2.2 Hz, 1H), 7.08 - 6.86 (m, 2H), 4.82 (d, J =10.9 Hz, 1H), 4.03 (s, 3H), 4.00 (d, J = 2.6 Hz, 3H), 3.75 (td, J =11.1, 9.0 Hz, 1H), 2.63 - 2.38 (m, 2H), 2.18 - 1.84 (m, 2H), 1.24 - 1.12(m, 3H) ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ -76.90, -79.76, -136.20(ddd, J = 19.2, 9.1, 5.7 Hz), -136.61 (ddd, J = 19.3, 9.4, 5.6 Hz),-153.43 --153.56 (m), -153.95 - -154.06 (m) ppm. ESI-MS m/z calc.488.1371, found 489.2 (M+1)⁺; 487.1 (M-1)⁻.

Step 8

Methylrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(200 mg, 0.41 mmol) was dissolved in methanolic ammonia (2.2 mL of 13 M,28.6 mmol). The solution was stirred at ambient temperature overnightthen concentrated in vacuo and the residue azeotroped with MeOH (3 × 5mL) to giverac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(108 mg, 56%, mixture of four isomers) as a light-yellow solid. ¹H NMR(300 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.19(dd, J = 5.6, 2.3 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.85 (d, J = 8.5Hz, 1H), 7.09 - 6.85 (m, 2H), 5.60 (s, 1H), 4.80 (d, J = 10.9 Hz, 1H),4.00 (d, J = 2.6 Hz, 3H), 3.74 (q, J = 10.8 Hz, 1H), 2.63 - 2.37 (m,2H), 1.99 (ddt, J = 37.8, 14.5, 7.3 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H)ppm; ¹⁹F NMR (376 MHz, Chloroform-d) δ -76.93, -79.78, -136.32 (ddd, J =19.5, 9.5, 5.8 Hz), -136.69 (ddd, J = 19.3, 9.4, 5.6 Hz), -153.54 (dd, J= 19.1, 6.3 Hz), -154.05 (d, J = 19.6 Hz) ppm. ESI-MS m/z calc.473.1374, found 474.15 (M+1)⁺; 472.15 (M-1)⁻.

Step 9

rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(108 mg, 0.23 mmol) was separated by chiral SFC using a Lux Cellulose-2column, 5um particle size, 25 cm x 10 mm from Phenomenex, Inc. to givetwo single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 3.22 min):rel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(63, 29 mg, 27%); ESI-MS m/z calc. 473.1374, found 474.4 (M+1)⁺ and472.4 (M-1)⁻.

Second Eluting Isomer (rt = 4.63 min):rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-ethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(64, 35 mg, 32%); ESI-MS m/z calc. 473.1374, found 474.4 (M+1)⁺ and472.4 (M-1)⁻.

The following compounds were made using a method similar to thatdescribed in Example 9, except that trimethylacetaldehyde was used asthe starting material in place of 1,1,1-trifluoro-2-butanone in step 1.In step 9, purification was performed by chiral SFC using a(R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x 21.2 mm from RegisTechnologies on a Minigram SFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 65rel-(2S,3R,5S)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(first eluting isomer by SFC on Whelk01 column, rt = 1.18 min) ESI-MSm/z calc. 433.1813, found 434.2 (M+1)⁺; 432.3 (M-1)⁻; Retention time:3.23 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.46 (d, J =5.5 Hz, 1H), 8.18 (dd, J = 5.6, 2.2 Hz, 1H), 8.13 (s, 1H), 7.93 (d, J =2.2 Hz, 1H), 7.25 (dd, J = 8.8, 5.8 Hz, 1H), 7.07 - 6.95 (m, 1H), 4.75(d, J = 10.7 Hz, 1H), 3.99 - 3.85 (m, 1H), 3.89 (s, 3H), 3.06 (d, J =5.0 Hz, 3H), 2.51 (dd, J = 13.2, 11.7 Hz, 1H), 2.42 (dd, J = 13.2, 8.3Hz, 1H), 1.68 (s, 3H) ppm. 66rel-(2R,3S,5R)-4-[[5-tert-butyl-3-(3,4-difluoro-2-methoxy-phenyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(second eluting isomer by SFC on Whelk01 column, rt = 1.68 min) ESI-MSm/z calc. 433.1813, found 434.2 (M+1)⁺; 432.3 (M-1)⁻; Retention time:3.23 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.48 (s, 1H), 8.36 (d, J =5.5 Hz, 1H), 8.08 - 8.00 (m, 2H), 7.86 (d, J = 2.2 Hz, 1H), 7.14 (dd, J= 8.8, 5.9 Hz, 1H), 6.92 (dd, J = 8.8, 8.1 Hz, 1H), 4.71 (d, J = 9.7 Hz,1H), 4.01 - 3.91 (m, 1H), 3.84 (s, 3H), 2.97 (d, J = 5.1 Hz, 3H), 2.77(dd, J = 13.9, 8.4 Hz, 1H), 2.03 (dd, J = 13.8, 11.7 Hz, 1H), 1.56 (s,2H) ppm.

Example 10rel-(2S,3R,5S)-4-[[3-(4-Fluoro-2-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(67) andRel-(2R,3S,5R)-4-[[3-(4-Fluoro-2-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(68)

Step 1

Triflic anhydride (1.5 mL, 8.92 mmol) was added dropwise to a solutionof ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.66 g, 6.91 mmol) and DIPEA (3.6 mL, 20.67 mmol) in DCM (50 mL)stirring at -78° C. After 3 hours saturated aqueous NaHCO₃ was added,the layers separated and the aqueous layer extracted with DCM. Thecombined organic layers were dried (MgSO₄), filtered and concentrated invacuo to give ethyl2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(2.573 g), which was used in the next step without further purification.

Step 2

A solution of ethyl2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(2.573 g, 6.91 mmol), (4-fluoro-2-methoxy-phenyl)boronic acid (1.84 g,10.83 mmol), Pd(PPh₃)₄ (600 mg, 0.52 mmol) and Na₂CO₃ (1.8 g, 16.98mmol) in PhMe (30 mL), MeOH (3 mL) and H₂O (3 mL) was degassed, thenheated at 80° C. for 16 hours. The reaction was cooled to ambienttemperature, diluted with EtOAc, the layers separated and the organiclayer washed with brine, dried (MgSO₄), filtered and concentrated invacuo. Purification by flash chromatography (80 g SiO₂, 0 to 20% EtOAcin petrol) gave ethyl4-(4-fluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(1.64 g, 68% over two steps) as a yellow oil. ESI-MS m/z calc.348.09848, found 349.2 (M+1)⁺.

Step 3

EtOH (45 mL) was added to a flash containing ethyl4-(4-fluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(1.64 g, 4.71 mmol) and Pd/C (500 mg, 0.47 mmol). The mixture wasdegassed then stirred under a balloon of hydrogen for 24 hours. Themixture was filtered through Celite, washing with EtOH, and concentratedin vacuo. Pd/C (500 mg, 0.47 mmol) was added to the residue, and themixture was suspended in EtOH (45 mL). The mixture was degassed thenstirred under a balloon of hydrogen for 24 hours. The mixture wasfiltered through Celite, washing with EtOH, and concentrated in vacuo togive ethylrac-(2S,3S,5R)-3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.53 g, 93%) as an off-white solid. ESI-MS m/z calc. 350.11414, found351.2 (M+1)⁺.

Step 4

A solution of ethylrac-(2S,3S,5R)-3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(10 mg, 0.029 mmol) and KOt-Bu (192 mg, 1.711 mmol) in tert-butanol (0.3mL) was stirred at ambient temperature for 30 mins. The reaction wasdiluted in EtOAc and quenched by addition of saturated aqueous NH4Clsolution. This process was repeated a further 19 times and the 20reactions combined for the rest of the work-up. The layers wereseparated and the aqueous layer extracted with EtOAc. The aqueous layerwas then acidified with 1 M HCl and extracted again. The combinedorganic layers were dried (MgSO₄), filtered and concentrated in vacuo togiverac-(2R,3S,5R)-3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (186 mg) as an orange residue, in an 9:1 diastereomeric ratio,which was taken on to the next step without further purification.

Step 5

To a solution ofrac-(2R,3S,5R)-3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (222 mg in 9:1 diastereomeric ratio, 0.69 mmol) in DCM (7.0 mL) wasadded DMF (10 µL, 0.13 mmol) and oxalyl chloride (200 µL, 2.29 mmol).The reaction was stirred at ambient temperature for 30 mins before beingconcentrated in vacuo. The residue was diluted in DCM (5 mL) and addeddropwise to a solution of methyl 4-aminopyridine-2-carboxylate (160 mg,1.05 mmol) and Et₃N (500 µL, 3.59 mmol) in DCM (2.0 mL) stirring at 0°C. DMAP (8 mg, 0.06548 mmol) was added and the reaction stirred at 0° C.for 10 mins, then warmed to ambient temperature and stirred for afurther 16 hours. The reaction mixture was diluted in DCM and washedwith 2 M HCl solution. The organic layer was dried (MgSO₄), filtered andconcentrated in vacuo directly onto silica gel. Purification by flashchromatography (40 g SiO₂, 0 to 100% EtOAc in petrol) gave methylrac-(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(154 mg, 49%) as a 9:1 mixture of diastereomers. ESI-MS m/z calc.456.13083, found 457.3 (M+1)⁺; 455.2 (M-1)⁻.

Step 6

Methylrac-(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(154 mg in a 9:1 mixture of diastereomers, 0.34 mmol) was dissolved inmethanolic ammonia (2.0 mL of 7 M, 14.00 mmol) and the solution stirredat ambient temperature overnight, then the mixture was concentrated invacuo to giverac-(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,as a mixture of diasteromers. ESI-MS m/z calc. 441.13116, found 442.1(M+1)⁺; 440.3 (M-1)⁻.

Step 7

The enantiomers of the major diastereomer ofrac-(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(15 mg, 0.03398 mmol) were separated by chiral SFC using a ChiralpakAS-H column, 5um particle size, 25 cm x 21.2 mm from Daicel Corporationto give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 1.44 min):rel-(2S,3R,5S)-4-[[3-(4-fluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(67, 3.2 mg, 42%); ESI-MS m/z calc. 441.13116, found 442.8 (M+1)⁺; 440.8(M-1)⁻; Retention time: 2.98 mins. ¹H NMR (500 MHz, DMSO-d₆) δ 10.28 (s,1H), 8.37 (d, J = 5.4 Hz, 1H), 8.08 - 7.94 (m, 2H), 7.56 (s, 1H), 7.54 -7.45 (m, 1H), 7.20 (t, J = 7.6 Hz, 1H), 6.76 (dd, J = 11.3, 2.5 Hz, 1H),6.64 (td, J = 8.6, 2.6 Hz, 1H), 5.10 (d, J = 8.4 Hz, 1H), 4.22 - 4.06(m, 1H), 3.77 (s, 3H), 2.91 (t, J = 12.3 Hz, 1H), 2.24 (dd, J = 11.6,6.7 Hz, 1H), 1.49 (s, 3H) ppm.

Second Eluting Isomer (rt = 1.63 min):rel-(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(68, 4.1 mg, 52%). ESI-MS m/z calc. 441.13116, found 442.8 (M+1)⁺; 440.8(M-1)⁻; Retention time: 2.98 mins.

The following compounds were made using the method described in Example10, taking forward the minor diastereoisomer formed in step 4. In step7, purification was performed by chiral SFC using a (R,R)-Whelk-O1column, 5 µm particle size, 25 cm x 21.1 mm from Daicel on a MinigramSFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 69rel-(2R,3R,5S)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 441.13116,found 442.1 (M+1)⁺; 440.2 (M-1)⁻; Retention time: 2.85 minutes ¹H NMR(500 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.08 -7.94 (m, 2H), 7.56 (s, 1H), 7.54 - 7.45 (m, 1H), 7.20 (t, J = 7.6 Hz,1H), 6.76 (dd, J = 11.3, 2.5 Hz, 1H), 6.64 (td, J = 8.6, 2.6 Hz, 1H),5.10 (d, J = 8.4 Hz, 1H), 4.22 - 4.06 (m, 1H), 3.77 (s, 3H), 2.91 (t, J= 12.3 Hz, 1H), 2.24 (dd, J = 11.6, 6.7 Hz, 1H), 1.49 (s, 3H) ppm.(first eluting isomer by SFC on (R,R)-Whelk-O1 column, rt = 1.44 min) 70rel-(2S,3S,5R)-4-[[3-(4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 441.13116,found 442.2 (M+1)⁺; 440.7 (M-1)⁻; Retention time: 2.85 minutes (secondeluting isomer by SFC on (R,R)-Whelk-O1 column, rt = 1.63 min)

The following compounds were made using the method described in Example10, except that2-(4-fluoro-2-methoxy-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas used as coupling partner in the Suzuki coupling step 2. In step 4,THF was used as solvent rather than tert-butanol. In step 7,purification was performed by chiral SFC using a (R,R)-Whelk-O1 column,5 µm particle size, 25 cm x 21.1 mm from Daicel on a Minigram SFCinstrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 71rel-(2S,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 455.14682,found 456.2 (M+1)⁺; 454.2 (M-1)⁻; Retention time: 3.05 minutes (firsteluting isomer by SFC on (R,R)-Whelk-O1 column, rt = 1.05 min) 72rel-(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 455.14682,found 456.2 (M+1)⁺; 454.2 (M-1)⁻; Retention time: 3.06 minutes ¹H NMR(500 MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.48 (dd, J = 5.5, 0.6 Hz, 1H), 8.24(dd, J = 2.2, 0.6 Hz, 1H), 8.04 (d, J = 2.8 Hz, 1H), 7.81 (dd, J = 5.5,2.2 Hz, 1H), 7.65 - 7.55 (m, 1H), 7.26 (dd, J = 8.7, 6.5 Hz, 1H), 7.02(t, J = 8.8 Hz, 1H), 4.64 (d, J = 10.1 Hz, 1H), 4.15 - 4.04 (m, 1H),3.63 (s, 3H), 2.49 - 2.46 (m, 1H), 2.33 (t, J = 12.4 Hz, 1H), 2.11 (d, J= 2.0 Hz, 3H), 1.58 (s, 3H) ppm. (second eluting isomer by SFC on(R,R)-Whelk-O1 column, rt = 1.73 min)

The following compounds were made using the method described in Example10, except that2-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas used as coupling partner in the Suzuki coupling step 2 and theconditions used for the epimerization/hydrolysis step 4 are similar tothe ones used in Example 2 step 7. In step 7, purification was performedby chiral SFC using a (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x21.1 mm from Daicel on a Minigram SFC instrument from BergerInstruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 73rel-(2S,3R,5S)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 477.11234, found 478.6 (M+1)⁺; 476.6 (M-1)⁻; Retentiontime: 3.03 minutes ¹H NMR (500 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.48 (d, J= 5.5 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.83(dd, J = 5.5, 2.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.56 - 7.49 (m,1H), 7.42 - 7.07 (m, 3H), 4.69 (d, J = 10.1 Hz, 1H), 4.05 (ddd, J =11.8, 10.1, 8.1 Hz, 1H), 2.57 - 2.51 (m, 1H), 2.43 (dd, J = 12.8, 8.2Hz, 1H), 1.57 (s, 3H) ppm. (first eluting isomer by SFC on(R,R)-Whelk-O1 column, rt = 2.61 min) 74rel-(2R,3S,5R)-4-[[3-[2-(difluoromethoxy)-4-fluorophenyl]-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 477.11234,found 478.6 (M+1)⁺; 476.6 (M-1)⁻; Retention time: 3.04 minutes (secondeluting isomer by SFC on (R,R)-Whelk-O1 column, rt = 3.32 min)

The following compounds were made using the method described in Example10, except that (2,4-difluoro-3-methyl-phenyl)boronic acid was used ascoupling partner in the Suzuki coupling step 2 and the conditions usedfor the epimerization/hydrolysis step 4 are similar to the ones used inExample 1 step 3:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 75rel-(2S,3R,5S)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 443.12683,found 444.6 (M+1)⁺; 442.7 (M-1)⁻; Retention time: 3.12 minutes ¹H NMR(500 MHz, DMSO-d₆) δ 10.46 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.26 (d, J= 2.2 Hz, 1H), 8.11 - 7.99 (m, 1H), 7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.60(d, J = 2.8 Hz, 1H), 7.31 (td, J = 8.5, 6.3 Hz, 1H), 7.05 (d, J = 8.7Hz, 1H), 4.66 (d, J = 10.1 Hz, 1H), 4.07 - 3.94 (m, 1H), 2.56 - 2.44 (m,2H), 2.12 (s, 3H), 1.57 (s, 3H) ppm. (first eluting isomer by SFC onChiralpak AS-H column, rt = 2.89 min) 76rel-(2R,3S,5R)-4-[[3-(2,4-difluoro-3-methyl-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 443.12683,found 444.6 (M+1)⁺; 442.7 (M-1)⁻; Retention time: 3.12 minutes (secondeluting isomer by SFC on Chiralpak AS-H column, rt = 3.71 min)

Example 11 Rel-(2s,3r,5s)-4-[[3-(3-Ethyl-4-Fluoro-2-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(77) and rel-(2R,3S,5R)-4-[[3-(3-Ethyl-4-Fluoro-2-Methoxyphenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(78)

Step 1 and 2

To a stirred solution of ethyl2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(10 g, 26.865 mmol) in 1,4-dioxane (150 mL), Potassium acetate (8 g,81.514 mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(27 g, 106.32 mmol) were added. The reaction mixture was de-gassed byargon gas then Pd(dppf)Cl₂ (983 mg, 1.3434 mmol) was added to thisreaction mixture and heated to 80° C. under argon for 15 min. Reactionwas monitored by TLC. Reaction was allowed to room temperature. Thendiluted with EtOAc (500 mL) and water (300 mL). Then filtered throughcelite bed, two layers were separated and the aqueous layer wasextracted with EtOAc (300 mL). The combined organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum.

The crude product was dissolved in THF (30 mL) and H₂O (15 mL), cooledto 0-5° C. NaIO₄ (17 g, 79.479 mmol) was added in the reaction mixtureportion wise and stirred it at room temperature for 15 min. Then HCl (10mL of 1 M, 10.000 mmol) was added and reaction mass was stirred for 4hours. Then reaction mass was diluted with water (200 mL) and EtOAc (500mL). Layers were separated. Organic layer was washed with brinesolution. Organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure. Crude mass was purified by silicagel chromatography using 2-10% EtOAc in hexane to get a yellow solid,this was washed with hexane to get[5-ethoxycarbonyl-2-methyl-2-(trifluoromethyl)-3H-furan-4-yl]boronicacid (2.5 g, 27%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (s,2H), 4.23 (q, J = 7.1 Hz, 2H), 3.11 (d, J = 18.2 Hz, 1H), 2.85 (d, J =18.24 Hz, 1H), 1.49 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H) ppm.

Step 3

To a stirred solution of 1-bromo-3-ethyl-4-fluoro-2-methoxy-benzene (3g, 12.87 mmol) and[5-ethoxycarbonyl-2-methyl-2-(trifluoromethyl)-3H-furan-4-yl]boronicacid (3.79 g, 14.16 mmol) in DME (15 mL) was added K₃PO₄ (7.65 g, 36.04mmol). The mixture was degassed with N₂ gas for 5 mins followed byaddition of PdCl₂(dtbpf) (838.86 mg, 1.29 mmol) and heated to 100° C.for 4 h. The reaction mixture was filtered through a celite pad, thefiltrate was diluted with water (50 mL) and the aqueous layer extractedwith EtOAc (100 mL). The organic layer was dried (MgSO₄), filtered andevaporated in vacuo. Purification by flash chromatography (SiO₂, 0 to 3%EtOAc in hexane) gave ethyl4-(3-ethyl-4-fluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(1.5 g, 31%) as light yellow liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.1823(t, J = 7 Hz, 1H), 6.9648 (t, J = 8.8 Hz, 1H) 4.0401 (q, J = 6.9 Hz,2H), 3.5996 (s, 3H), 3.4321 (d, J = 17.6 Hz, 1H), 3.1492 (d, J = 17.6Hz, 1H), 2.6211-2.5858 (m, 2H), 1.614 (s, 3H), 1.1339 (t, J = 7.3 Hz,3H), 1.0159 (t, J = 7 Hz, 3H) ppm. ESI-MS m/z calc. 376.1298, found377.0 (M+1)⁺.

Step 4

To a stirred solution of ethyl4-(3-ethyl-4-fluoro-2-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(1.5 g, 3.99 mmol) in ethanol (50 mL) was added Pd(OH)₂ (4.5 g, 32.04mmol). The reaction was stirred at ambient temperature for 16 hours in aParr shaker under a 50 psi pressure of hydrogen. Reaction mass wasfiltered through celite bed, filtrate was evaporated under reducedpressure to get crude compound. Purification by flash chromatography(SiO₂, 30% EtOAc in hexane) gave ethylrac-(2S,3S,5R)-3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.3 g, 86%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.04 (t, J =6.9 Hz, 1H), 6.92 (t,J = 9 Hz, 1H) 4.95 (d, J = 8.9 Hz, 1H), 4.35-4.28(m, 1H), 3.80 (s, 3H), 3.70-3.59 (m, 2H), 2.63-2.54 (m, 3H), 2.31-2.26(m, 1H), 1.49 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H), 0.72 (t, J = 7 Hz, 3H)ppm. ESI-MS m/z calc. 378.1454, found 379.0 (M+1)⁺.

Step 5

To a stirred solution of ethylrac-(2S,3S,5R)-3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.2 g, 3.17 mmol) in MeOH (10 mL) was added cesium carbonate (2.07 g,6.34 mmol). The reaction was stirred at an ambient temperature for 1hthen it was heated at 50° C. for 16 h. The reaction mixture wasconcentrated in vacuo then water (5 mL) was added. The aqueous layer wasacidified with 1 M HCl, to neutral pH. The aqueous layer was extractedin 10% methanol-DCM mixture (2 × 50 mL) and the organic layer wasevaporated in vacuo to giverac-(2R,3S,5R)-3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (1 g, 75%) as a colourless liquid, which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 12.89 (s, 1H), 7.29-7.25(m,1H) 6.99 (t, J = 9 Hz, 1H), 4.44 (d, J = 10.4, 1H), 3.91-3.88 (m,1H), 3.70 (s, 3H), 2.64-2.58 (m, 2H), 2.49-2.42 (m, 1H), 2.27-1.98 (m,1H), 1.48 (s, 3H), 1.14 (t,J = 7.4 Hz, 3H) ppm. ESI-MS m/z calc.350.1141, found 351.0 (M+1)⁺.

Step 6

To a solution ofrac-(2R,3S,5R)-3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (100 mg, 0.29 mmol) in DCM (2.5 mL) stirring at 0° C. was added DMF(5 µL, 0.065 mmol) and oxalyl chloride (100 µL, 1.15 mmol). After 30mins the reaction mixture was concentrated in vacuo then diluted in DCM(2.3 mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (60 mg, 0.39 mmol), DMAP (4 mg, 0.033mmol) and Et₃N (250 µL, 1.79 mmol) in DCM (2 mL) stirring at 0° C. After10 mins the reaction was warmed to ambient temperature and stirred for16 h. The reaction mixture was concentrated onto silica gel and purifiedby flash chromatography (40 g SiO₂, 0 to 100 % EtOAc in heptane) to givemethylrac-(2R,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(109 mg, 72%). ESI-MS m/z calc. 484.16214, found 485.8 (M+1)⁺; 483.1(M-1)⁻.

Step 7

Methylrac-(2R,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(109 mg, 0.20 mmol) and ammonia (10 mL of 7 M, 70.00 mmol) were stirredat ambient temperature overnight. The reaction mixture was concentratedin vacuo to giverac-(2R,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(105 mg, containing 8% of an undesired minor isomer), which was usedwithout further purification. ESI-MS m/z calc. 469.16248, found 470.2(M+1)⁺; 468.2 (M-1)⁻.

Step 8

rac-(2R,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(105 mg, 0.22 mmol) was separated by chiral SFC using a Chiralpak AS-Hcolumn, 5um particle size, 25 cm × 10 mm from Daicel on a Minigram SFCinstrument from Berger Instruments to give two single isomers of unknownabsolute configuration:

First Eluting Isomer (rt = 3.22 min):rel-(2S,3R,5S)-4-[[3-(3-ethyl-4-fluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(77, 22.6 mg, 22%); ESI-MS m/z calc. 469.16248, found 470.2 (M+1)⁺;468.2 (M-1)⁻

Second Eluting Isomer (rt = 4.63 min):rel-(2R,3S,5R)-4-[[3-(3-ethyl-4-fluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(78, 20.7 mg, 20%); ESI-MS m/z calc. 469.16248, found 470.3 (M+1)⁺;468.2 (M-1)⁻.

Example 12Rac-(2r,3s,5r)-4-[[3-(2-Fluoro-6-Methoxy-Phenyl)-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(79)

Step 1

A mixture of ethyl2-methyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(1550 mg, 4.16 mmol), (2-fluoro-6-methoxy-phenyl)boronic acid (690 mg,4.06 mmol) and Pd(PPh₃)₂Cl₂ (160 mg, 0.23 mmol) in dioxane (35 mL) andsaturated aqueous NaHCO₃ (excess) was degassed and refilled withnitrogen (× 3 before catalyst added, then × 3 with catalyst). Thereaction mixture was heated at 80° C. for 24 hours before being cooledto ambient temperature and concentrated in vacuo. The residue wasredisolved in EtOAc and the solution washed with water/brine. The layerswere separated and the organic layer filtered through a celite cartridge(10 g), eluting with EtOAc, then concentrated in vacuo to give ethyl4-(2-fluoro-6-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(1.40 g, 97%), which was used without further purification. ESI-MS m/zcalc. 348.09848, found 349.1 (M+1)⁺.

Step 2

BBr₃ (6.30 mL of 1 M, 6.34 mmol) was added dropwise to an ice-cooledsolution of ethyl4-(2-fluoro-6-methoxy-phenyl)-2-methyl-2-(trifluoromethyl)-3H-furan-5-carboxylate(1450 mg, 4.16 mmol) in DCM (5.65 mL). Upon completion, the mixture wasquenched with water and sodium bicarbonate solution. The layers wereseparated and the aqueous layer extracted with DCM. The organic layerwas dried (MgSO₄) and concentrated in vacuo. The oil was dissolved inDCM (6.75 mL) and stirred at ambient temperature whilst TFA (1.014 g,685 µL, 8.90 mmol) was added. The mixture was heated to 45° C. for 30mins then quenched with sodium bicarbonate solution, extracted with DCMand the organic layer dried (MgSO₄) and concentrated in vacuo to give9-fluoro-2-methyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one(1.1 g, 92%) as a brown waxy solid, which was used without any furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.57 - 7.49 (m, 1H), 7.39 -7.19 (m, 2H), 3.86 -3.59 (m, 2H), 1.72 (d, J = 1.0 Hz, 3H) ppm.

Step 3

9-fluoro-2-methyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one(1100 mg, 3.82 mmol) was dissolved in MeOH (50 mL) and this solutionadded to Pd(OH)₂ (3 g, 21.4 mmol) in a 250 mL Parr vessel. The mixturewas shaken under 60 psi hydrogen at ambient temperature overnight. Thereaction mixture was filtered and concentrated in vacuo. The residue wasredissolved in ethanol (50 mL) and added to Pd/C (1.1 g), then shakenunder 60 psi hydrogen at ambient temperature for 60 hours before beingfiltered and concentrated in vacuo. Purification by flash chromatography(12 g SiO₂, 10 to 40% EtOAc in heptane) gaverac-(2R,3aS,9bS)-9-fluoro-2-methyl-2-(trifluoromethyl)-1,2,3a,9b-tetrahydro-4H-furo[2,3-c]chromen-4-one(190 mg, 17%), which was used without further purification. ESI-MS m/zcalc. 290.0566, found 291.1 (M+1)⁺.

Step 4

Cesium carbonate (430 mg, 1.32 mmol) was added to a stirred suspensionofrac-(2R,3aS,9bS)-9-fluoro-2-methyl-2-(trifluoromethyl)-1,2,3a,9b-tetrahydro-4H-furo[2,3-c]chromen-4-one(190 mg, 0.65 mmol) in ethanol (4 mL) and the mixture heated at 50° C.for 2 hours. The reaction was cooled to ambient temperature andconcentrated in vacuo. The residue was redissolved in ethanol (4 mL) andpotassium tert-butoxide (4 eq.) was added. The reaction was stirredovernight before being quenched with 1 M aqueous HCl (5 mL), dilutedwith EtOAc (10 mL) and the layers separated. The aqueous layer wasextracted with EtOAc (3 × 10 mL), and the combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,5R)-3-(2-fluoro-6-hydroxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (200 mg) as a white solid, which was used without furtherpurification.

Step 5

To a solution ofrac-(2R,3S,5R)-3-(2-fluoro-6-hydroxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (200 mg, 0.65 mmol) in acetonitrile (2 mL) was added K₂CO₃ (380 mg,2.75 mmol) and MeI (263 mg, 1.85 mmol). The reaction was heated to 80°C. for 6 hours in a sealed reaction vessel, then cooled to ambienttemperature, diluted in DCM and filtered. The filtrate was carefullyconcentrated in vacuo using a cold water bath to give methylrac-(2R,3S,5R)-3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(200 mg) as a yellow oil, which was used without further purification.

Step 6

Methylrac-(2R,3S,5R)-3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(200 mg, 0.59 mmol) was added to a stirred suspension of cesiumcarbonate (390 mg, 1.19 mmol) in ethanol (4 mL) and the mixture heatedat 50° C. for 2 hours. The reaction was cooled to ambient temperatureand concentrated in vacuo. The residue was dissolved in 1 M aqueous HCl(5 mL) and EtOAc (10 mL) and the layers separated. The aqueous layer wasextracted with EtOAc (3 × 10 mL) and the combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,5R)-3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (190 mg) as a white solid, which was used in the next step withoutfurther purification. ESI-MS m/z calc. 322.08282, found 321.1 (M-1)⁻.

Step 7

To a solution ofrac-(2R,3S,5R)-3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (190 mg, 0.59 mmol) in DCM (10 mL) stirring at ambient temperaturewas added DMF (4.6 µL, 0.059 mmol) and oxalyl chloride (160 µL, 1.83mmol). After 15 mins the reaction mixture was concentrated in vacuo, theresidue diluted in DCM (3 mL) and added dropwise over 5 mins to anice-cooled solution of methyl 4-aminopyridine-2-carboxylate (90 mg, 0.59mmol), DMAP (3.7 mg, 0.030 mmol) and NEt₃ (250 µL, 1.79 mmol) in DCM (5mL). After warming to ambient temperature overnight the reaction mixturewas diluted with DCM (50 mL) and washed with 2 M HCl solution (50 mL).The organic layer was passed through a phase separator cartridge and thefiltrate concentrated in vacuo to give methylrac-(2R,3S,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(250 mg), which was used without further purification. ESI-MS m/z calc.456.13083, found 457.1 (M+1)⁺.

Step 8

Methylrac-(2R,3S,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(250 mg, 0.55 mmol) was dissolved in methanolic ammonia (10 mL of 7 M,70.00 mmol) and stirred at ambient temperature for 6 hours. The solutionwas concentrated in vacuo before being purified fraction lynx (Ammoniashallow 5 gradient, in DMSO loading solvent) to giverac-(2R,3S,5R)-4-[[3-(2-fluoro-6-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(79, 3.2 mg, 1% over 5 steps). ¹H NMR (400 MHz, Chloroform-d) δ 8.61 (s,1H), 8.47 (d, J = 5.6 Hz, 1H), 8.19 (dd, J = 5.6, 2.2 Hz, 1H), 7.97 -7.87 (m, 2H), 7.26 (td, J = 8.4, 6.6 Hz, 1H), 6.81 - 6.70 (m, 2H), 5.64(s, 1H), 5.12 (d, J = 10.7 Hz, 1H), 4.05 (td, J = 11.5, 8.2 Hz, 1H),3.87 (s, 3H), 3.10 (t, J = 12.4 Hz, 1H), 2.14 (dd, J = 12.6, 8.1 Hz,1H), 1.66 (s, 3H) ppm. ESI-MS m/z calc. 441.13116, found 442.1 (M+1)⁺;440.3 (M-1)⁻.

Example 13 Rel-(2r,3s,5s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-Methyl-5-(2,2,2-Trifluoroethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(80), Rel-(2r,3s,5r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-Methyl-5-(2,2,2-Trifluoroethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(81), Rel-(2s,3r,5s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-Methyl-5-(2,2,2-Trifluoroethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(82) and Rel-(2s,3r,5r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-Methyl-5-(2,2,2-Trifluoroethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(83)

Step 1

TiCl₄ (20 mL of 1 M, 20.0 mmol) and Et₃N (2.77 mL, 19.9 mmol) were addedsequentially and dropwise to a solution of ethyl 2-diazo-3-oxo-butanoate(2.47 mL, 17.89 mmol) in DCM (100 mL) in a three-necked flask, stirringat -78° C. . After 1 h, a solution of Ti(OiPr)₄ (5.6 mL, 19.0 mmol) and4,4,4-trifluorobutan-2-one (2.33 g, 18.5 mmol) in DCM (20 mL) was addedto the mixture via dropping funnel. After a further 5 hours the reactionwas quenched by the addition of saturated aq. NH₄Cl solution. Theaqueous layer was separated and extracted (DCM) and the combinedorganics washed with brine, dried (MgSO₄) and concentrated in vacuo.Purification (80 g SiO₂, 0 to 20% EtOAc in heptane) gave ethyl2-diazo-7,7,7-trifluoro-5-hydroxy-5-methyl-3-oxo-heptanoate (2.5 g, 50%)as a colourless oil. ¹H NMR (400 MHz, Chloroform-d) δ 4.32 (q, J = 7.1Hz, 2H), 4.17 - 4.08 (m, 1H), 3.31 (d, J = 17.2 Hz, 1H), 3.09 (d, J =17.2 Hz, 1H), 2.63 - 2.37 (m, 2H), 1.42 (d, J = 1.2 Hz, 3H), 1.35 (t, J= 7.1 Hz, 3H) ppm.

Step 2

A suspension of rhodium tetraacetate (68 mg, 0.15 mmol) in benzene (60mL) was heated at 100° C. for 10 mins. A solution of ethyl2-diazo-7,7,7-trifluoro-5-hydroxy-5-methyl-3-oxo-heptanoate (2500 mg,8.858 mmol) in benzene (22 mL) was then added dropwise via droppingfunnel. After 2 hours the reaction was cooled to ambient temperature,filtered through celite, washing with DCM, and concentrated in vacuo.Purification by flash chromatography (40 g SiO₂, 0 to 20% EtOAc inheptane) gave ethyl5-methyl-3-oxo-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylate(1.5 g, 67%) as a colourless oil, in a 1:1 mixture of diastereomers. ¹HNMR (400 MHz, Chloroform-d) δ 4.67 - 4.55 (m, 1H), 4.38 - 4.18 (m, 2H),2.86 - 2.66 (m, 2H), 2.65 - 2.49 (m, 2H), 1.57 (dd, J = 52.9, 1.1 Hz,3H), 1.32 (td, J = 7.1, 2.4 Hz, 3H) ppm.

Step 3

Trifluoromethylsulfonyl trifluoromethanesulfonate (2.18 g, 7.72 mmol)was added to a solution of ethyl5-methyl-3-oxo-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylate(1.50 g, 5.90 mmol) and DIPEA (2.3 g, 17.8 mmol) in DCM (50 mL) stirringat -78° C. . After 4 hours saturated aq. NaHCO₃ solution was added, thelayers separated and the aqueous layer extracted with DCM, dried (MgSO₄)and concentrated in vacuo to give ethyl2-methyl-2-(2,2,2-trifluoroethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(2.1 g, 92%), which was used without any further purification.

Step 4

A mixture of ethyl2-methyl-2-(2,2,2-trifluoroethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(850 mg, 2.20 mmol),2-(3,4-difluoro-2-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(715 mg, 2.647 mmol) and Pd(PPh₃)₂Cl₂ (80 mg, 0.11 mmol) in dioxane (20mL) and saturated aqueous NaHCO₃ (2 mL) was degassed extensively andheated at 80° C. After 4 hours the reaction mixture was cooled toambient temperature and filtered through a celite cartridge washing withEtOAc, then concentrated in vacuo. The residue was purified by flashchromatography (40 g SiO₂, 0 to 20% EtOAc in heptane) to give ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl-2-(2,2,2-trifluoroethyl)-3H-furan-5-carboxylate(290 mg, 35%) as a clear oil. ESI-MS m/z calc. 380.1047, found 381.2(M+1)⁺.

Step 5

EtOH (10 mL) was added to a mixture of ethyl4-(3,4-difluoro-2-methoxy-phenyl)-2-methyl-2-(2,2,2-trifluoroethyl)-3H-furan-5-carboxylate(290 mg, 0.7625 mmol) and Pd/C (10 wt. % loading, 1000 mg, 0.94 mmol).The mixture was degassed and stirred under a balloon of hydrogenovernight. Further Pd/C (10 wt. % loading, 1000 mg, 0.94 mmol) wasadded, the mixture degassed and stirred under a balloon of hydrogen fora further 20 h. The mixture was passed through a celite cartridgerinsing with DCM, and the filtrate concentrated in vacuo and purified bycolumn chromatography (12g SiO₂, 0 to 40% EtOAc/Hexanes) to give ethylrac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylate(200 mg, 69%). ¹H NMR (400 MHz, Methanol-d₄) δ 6.95 - 6.81 (m, 2H), 4.86(d, J = 8.5 Hz, 1H), 4.27 - 4.15 (m, 1H), 4.09 (d, J = 2.7 Hz, 3H),3.84 - 3.63 (m, 2H), 3.00 - 2.86 (m, 1H), 2.88 - 2.73 (m, 1H), 2.51 (t,J = 12.8 Hz, 1H), 2.15 -2.05 (m, 1H), 1.47 (d, J = 1.5 Hz, 3H), 0.85 (t,J = 7.1 Hz, 3H) ppm. ESI-MS m/z calc. 382.12036, found 383.3 (M+1)⁺.

Step 6

A solution of ethylrac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylate(75 mg, 0.20 mmol) and potassium tert-butoxide (65 mg, 0.58 mmol) intert-butanol (2.2 mL) were stirred at ambient temperature for 6 h beforebeing quenched with saturated aq. NH₄Cl solution and diluted with EtOAc.The layers were separated and the aqueous layer and extracted withEtOAc. The aqueous layer was then acidified with 1 M HCl and extractedwith further EtOAc. The combined organic layers were dried (MgSO₄),filtered and concentrated in vacuo to affordrac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylicacid (68 mg, 98%) which was used without further purification. ESI-MSm/z calc. 354.08905, found 355.0 (M+1)⁺; 352.9 (M-1)⁻.

Step 7

To a solution ofrac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carboxylicacid (60 mg, 0.17 mmol) in DCM (5 mL) was added DMF (3 µL, 0.04 mmol)and oxalyl chloride (50 µL, 0.57 mmol). After 15 mins at ambienttemperature the reaction was concentrated in vacuo. The residue wasdiluted in DCM (2 mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (40 mg, 0.26 mmol), DMAP (2 mg, 0.016mmol) and Et₃N (150 µL, 1.08 mmol) in DCM (1 mL) stirring at 0° C. After10 mins at this temperature, the reaction was warmed to ambienttemperature and stirred for a further 40 mins before being diluted inDCM (50 mL) and washed with 2 M HCl solution (50 mL). The organic layerwas passed through a phase separator cartridge and concentrated in vacuoto give methylrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(70 mg, 85%), which was used without further purification. ESI-MS m/zcalc. 488.13705, found 489.3 (M+1)⁺; 487.3 (M-1)⁻.

Step 8

Methylrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(70 mg, 0.14 mmol) was stirred in methanolic ammonia (2 mL of 7 M, 14.00mmol) at ambient temperature overnight . Further methonolic ammonia (2mL of 7 M, 14.00 mmol) was added and the reaction left for 6 hoursbefore being concentrated in vacuo to give a mixture ofrac-(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideandrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(60 mg, 88%), which was used without further purification. ESI-MS m/zcalc. 473.1374, found 474.3 (M+1)⁺; 472.3 (M-1)⁻.

Step 9

The mixture ofrac-(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideandrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideobtained in Step 8 (60 mg, 0.1267 mmol) was separated by chiral SFCusing a (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm x 21.2 mm fromRegis Technologies on a Minigram SFC instrument from Berger Instrumentsto give:

First Eluting Isomers (rt = 0.91 min): a mixture of bothrel-(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(80) andrel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(82), that needed further separation.

Second Eluting Isomer (rt = 1.29 min):rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(81, 9.9 mg, 16.5%). ¹H NMR (500 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.34(d, J = 5.5 Hz, 1H), 8.06 (dd, J = 5.5, 2.2 Hz, 1H), 7.79 (d, J = 2.2Hz, 1H), 7.72 (d, J = 4.1 Hz, 1H), 6.87 (ddd, J = 8.1, 5.5, 2.1 Hz, 1H),6.77 (td, J = 9.1, 7.2 Hz, 1H), 5.60 - 5.55 (m, 1H), 4.51 (d, J = 10.0Hz, 1H), 3.87 (d, J = 2.4 Hz, 3H), 3.80 (q, J = 9.8 Hz, 1H), 2.48 (dddd,J = 26.3, 15.2, 11.0, 4.2 Hz, 2H), 2.22 (d, J = 9.8 Hz, 2H), 1.45 (s,3H) ppm. ESI-MS m/z calc. 473.1374, found 474.4 (M+1)⁺; 472.4 (M-1)⁻.

Third Eluting Isomer (rt = 1.45 min):rel-(2S,3R,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(83, 4.8 mg, 8%). ¹H NMR (500 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.33(d, J = 5.5 Hz, 1H), 7.95 - 7.89 (m, 1H), 7.84 (s, 1H), 7.72 (s, 1H),6.87 (s, 1H), 6.81 - 6.72 (m, 1H), 5.46 (s, 1H), 4.53 (d, J = 10.3 Hz,1H), 3.85 (d, J = 2.4 Hz, 3H), 3.66 (q, J = 10.5 Hz, 1H), 2.50 - 2.39(m, 3H), 2.01 (t, J = 12.4 Hz, 1H), 1.47 (s, 3H) ppm. ESI-MS m/z calc.473.1374, found 474.4 (M+1)⁺; 472.4 (M-1)⁻.

The first eluting peak was further separated by chiral SFC using a LuxCellulose-2 column, 5 µm particle size, 25 cm x 10 mm from Phenomenex,Inc. to give two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 4.05 min):rel-(2R,3S,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(80, 3.6 mg, 6%). ¹H NMR (500 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.48(d, J = 5.5 Hz, 1H), 8.09 (dd, J = 5.5, 1.9 Hz, 1H), 7.99 (d, J = 2.1Hz, 1H), 7.93 (s, 1H), 7.02 (ddd, J = 8.0, 5.5, 2.1 Hz, 1H), 6.91 (td, J= 9.1, 7.3 Hz, 1H), 5.62 (s, 1H), 4.68 (d, J = 10.4 Hz, 1H), 4.00 (d, J= 2.5 Hz, 3H), 3.81 (td, J = 11.0, 8.2 Hz, 1H), 2.65 - 2.54 (m, 3H),2.21 - 2.12 (m, 1H), 1.62 (s, 3H) ppm. ESI-MS m/z calc. 473.1374, found474.3 (M+1)⁺; 472.4 (M-1)⁻.

Second Eluting Isomer (rt = 4.39 min):rel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(2,2,2-trifluoroethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(82, 7 mg, 11.7%). ¹H NMR (500 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.49(d, J = 5.5 Hz, 1H), 8.21 (dd, J = 5.6, 2.0 Hz, 1H), 7.94 (d, J = 2.2Hz, 1H), 7.89 (s, 1H), 7.02 (ddd, J = 8.1, 5.5, 2.1 Hz, 1H), 6.91 (td, J= 9.1, 7.2 Hz, 1H), 5.68 (s, 1H), 4.66 (d, J = 9.9 Hz, 1H), 4.02 (d, J =2.4 Hz, 3H), 4.02 - 3.90 (m, 1H), 2.63 (dddd, J = 26.4, 15.2, 11.0, 4.2Hz, 2H), 2.36 (d, J = 9.7 Hz, 2H), 1.59 (s, 3H) ppm. ESI-MS m/z calc.473.1374, found 474.4 (M+1)⁺; 472.4 (M-1)⁻.

The following compounds were made using a method similar to thatdescribed in Example 13, except that 3,3-difluoro-butan-2-one was usedas the starting material in place of 4,4,4-trifluorobutan-2-one instep 1. In step 6, ethanol was used as solvent rather than tert-butanol:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 84rel-(2R,3S,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 455.14682, found 456.6 (M+1)⁺; 454.7 (M-1)⁻; Retentiontime: 3.01 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.40 (dd, J = 5.4,2.4 Hz, 1H), 8.21 - 8.05 (m, 1H), 7.92 (q, J = 2.4 Hz, 1H), 7.01 (td, J= 5.9, 2.9 Hz, 1H), 6.94 -6.73 (m, 1H), 4.59 (dd, J = 10.6, 2.8 Hz, 1H),3.89 (q, J = 2.3 Hz, 3H), 3.85 (dd, J = 8.9, 5.7 Hz, 1H), 2.62 - 2.49(m, 1H), 2.16 (dt, J = 12.7, 5.4 Hz, 1H), 1.70 (td, J = 19.0, 2.9 Hz,3H), 1.51 (d, J = 2.9 Hz, 3H) ppm. (first eluting peak by SFC on Whelk01column, rt = 1.18 min; first eluting isomer by SFC on Lux Cellulose-2column, rt = 2.35 min) 85rel-(2S,3R,5S)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 455.14682, found 456.6 (M+1)⁺; 454.7 (M-1)⁻; Retentiontime: 2.89 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.30 (dd, J = 5.6,1.9 Hz, 1H), 7.73 (s, 1H), 7.69 - 7.64 (m, 1H), 6.75 - 6.63 (m, 1H),6.60 (tdd, J = 9.2, 7.1, 2.0 Hz, 1H), 4.80 - 4.74 (m, 1H), 4.36 (dddd, J= 12.4, 9.5, 7.1, 2.0 Hz, 1H), 4.03 (t, J = 2.6 Hz, 3H), 2.62 -2.47 (m,1H), 1.95 (ddd, J = 12.5, 7.3, 1.7 Hz, 1H), 1.77 (td, J = 19.4, 2.1 Hz,3H), 1.44 (d, J = 1.9 Hz, 3H) ppm. (first eluting peak by SFC on Whelk01column, rt = 1.18 min; second eluting isomer by SFC on Lux Cellulose-2column, rt = 3.69 min) 86rel-(2R,3S,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 455.14682, found 456.6 (M+1)⁺; 454.7 (M-1)⁻; Retentiontime: 2.89 minutes ¹H NMR (500 MHz, Methanol-d₄) δ 8.25 (d, J = 5.6 Hz,1H), 7.69 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 5.5, 2.2 Hz, 1H), 6.64(ddd, J = 8.0, 5.6, 1.9 Hz, 1H), 6.55 (td, J = 9.2, 7.2 Hz, 1H), 4.74(dd, J = 9.9, 1.2 Hz, 1H), 4.34 -4.25 (m, 1H), 3.97 (d, J = (secondeluting isomer by SFC on Whelk01 column, rt = 1.39 min) 2.6 Hz, 3H),2.50 (t, J = 12.7 Hz, 1H), 1.91 (dd, J = 12.5, 7.1 Hz, 1H), 1.72 (t,J=19.5 Hz, 3H), 1.39 (s, 3H) ppm. 87rel-(2S,3R,5R)-4-[[5-(1,1-difluoroethyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 455.14682, found 456.2 (M+1)⁺; 454.1 (M-1)⁻; Retentiontime: 2.98 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.33 (d, J = 5.5 Hz,1H), 8.05 (dq, J = 4.4, 2.3 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 6.93(ddd, J = 8.1, 5.5, 2.1 Hz, 1H), 6.77 (td, J = 9.2, 7.4 Hz, 1H), 4.51(d, J = 10.6 Hz, 1H), 3.83 - 3.67 (m, 4H), 3.14 - 3.06 (m, 1H), 3.04 (s,2H), 2.49 (t, J = 12.4 Hz, 1H), 2.12 - 2.04 (m, 1H), 1.64 (d, J = 19.0Hz, 2H), 1.43 (s, 3H) ppm. (third eluting isomer by SFC on Whelk01column, rt = 1.81 min)

Example 14Rel-(2s,3r,4r,5s)-4-[[3-(3,4-Difluoro-2-Isopropoxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]pyridine-2-Carboxamide(88) andRel-(2r,3s,4s,5r)-4-[[3-(3,4-Difluoro-2-Isopropoxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(89)

Step 1

MeOH (620 mL) was added into a Parr shaker flask shaker containingrac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one(32.3 g, 100.9 mmol) and Pd(OH)₂ (24 g, 34.18 mmol). The mixture wasdegassed and repressurised to 55 psi H₂, and left to shake for 2 days.The mixture was filtered, washing the catalyst with DCM followed byEtOAc and methanol, and the filtrate concentrated in vacuo to givemethylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(34 g, 95%). ¹H NMR (500 MHz, Methanol-d₄) δ 7.05 (ddt, J = 9.1, 7.5,2.0 Hz, 1H), 6.57 (ddd, J = 10.1, 9.0, 7.6 Hz, 1H), 5.01 (d, J = 6.0 Hz,1H), 4.34 (dd, J = 8.5, 6.0 Hz, 1H), 3.49 (s, 3H), 2.93 (h, J = 7.4 Hz,1H), 1.50 (d, J = 1.2 Hz, 3H), 0.89 (dd, J = 7.6, 1.9 Hz, 3H) ppm.ESI-MS m/z calc. 354.08905, found 353.6 (M-1)⁻.

Step 2

2-bromopropane (210 µL, 2.24 mmol) was added to a solution of methylrac-(2S,3S,4S,SR)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(260 mg, 0.73 mmol) and K₂CO₃ (305 mg, 2.21 mmol) in DMF (3.7 mL). Thereaction was heated at 60° C. for 2 hours before further 2-bromopropane(210 µL, 2.24 mmol) was added. After a further 2 hours stirring at 60°C. the reaction was cooled to ambient temperature and diluted with NH₄Clsolution. The layers were separated and the aqueous layer extracted withEtOAc. The combined organic layers were washed with brine, dried(MgSO₄), filtered and concentrated in vacuo to afford methylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(271 mg) as an oil which was used without further purification.

Step 3

To a solution of methylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(270 mg, 0.68 mmol) in tert-butanol (5 mL) strring at ambienttemperature was added potassium tert-butoxide (155 mg, 1.38 mmol). Thereaction was stirred for 2 hours before being diluted in EtOAc andquenched by the addition of 1 M HCl. The layers were separated and theaqueous layer extracted with EtOAc. The combined organic layers weredried (MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-isopropoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (246 mg, 94%) as a yellow residue. ESI-MS m/z calc. 382.12036,found 381.6 (M-1)⁻.

Step 4

To a solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (246 mg, 0.64 mmol) in DCM (6 mL) stirring at 0° C. was added DMF(5 µL, 0.065 mmol) and oxalyl chloride (170 µL, 1.95 mmol). After 30mins the reaction was concentrated in vacuo and the residue diluted inDCM (4 mL). This solution was added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (145 mg, 0.95 mmol) and Et₃N (450 µL,3.229 mmol) in DCM (2 mL) stirring at 0° C. DMAP (7 mg, 0.057 mmol) wasadded and the reaction stirred at this temperature for 10 mins beforebeing warmed to ambient temperature and stirred overnight. The reactionmixture was diluted with DCM and washed with 1 M HCl solution. Theorganic layers were dried (MgSO₄), filtered and concentrated in vacuo,directly onto silica gel. Purification by flash chromatography (24 gSiO₂, 0 to 100% EtOAc in petrol) gave methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(133 mg, 40%). ESI-MS m/z calc. 516.16833, found 517.7 (M+1)⁺; 515.8(M-1)⁻.

Step 5

Methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(133 mg, 0.26 mmol) was stirred in methanolic ammonia (8 mL of 7 M,56.00 mmol) at ambient temperature overnight. The reaction mixture wasconcentrated in vacuo to giverac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(130 mg, 100%). ESI-MS m/z calc. 501.1687, found 502.6 (M+1)⁺.

Step 6

rac-(2R,3S,4S,5R)-(4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(130 mg, 0.26 mmol) was separated by chiral SFC using a (R,R)-Whelk-O1column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies on aMinigram SFC instrument from Berger Instruments to give:

First Eluting Isomers (rt = 0.84 min): rel-(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(88, 38 mg, 29%). ESI-MS m/z calc. 501.1687, found 502.2 (M+1)⁺; 500.2(M-1)⁻.

Second Eluting Isomer (rt = 1.29 min): rel-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-isopropoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(89, 34.2 mg, 26%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.49 (d,J = 5.5 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H),7.80 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.20 - 7.10(m, 2H), 5.09 (d, J = 10.5 Hz, 1H), 4.62 - 4.51 (m, 1H), 4.30 (dd, J =10.5, 7.5 Hz, 1H), 2.74 (p, J = 7.5 Hz, 1H), 1.61 (s, 3H), 1.35 (d, J =6.1 Hz, 3H), 1.22 (d, J = 6.1 Hz, 3H), 0.71 (d, 3H) ppm. ESI-MS m/zcalc. 501.1687, found 502.2 (M+1)⁺; 500.2 (M-1)⁻.

Example 15Rel-(2s,3r,4r,5s)-4-[[3-(3,4-Difluorophenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(90) AndRel-(2r,3s,4s,5r)-4-[[3-(3,4-Difluorophenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(91)

Step 1

To a degassed solution of ethylrac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate(2 g, 4.85 mmol) in toluene (25 mL) was added K₃PO₄ (8.5 mL of 2 M,17.00 mmol) and (3,4-difluorophenyl)boronic acid (860 mg, 5.45 mmol).The mixture was further degassed for 10 mins beforetetrakis(triphenylphosphine)palladium(0) (285 mg, 0.25 mmol) was added.The reaction was stirred at 100° C. for 2 hours before the solvent wasremoved in vacuo and the residue diluted with water. The aqueous layerwas extracted with EtOAc (3 × 100 mL) and the combined organic layerswere dried (MgSO₄) and concentrated in vacuo. Purification by flashchromatography (SiO₂, 2 to 5% EtOAc in hexane) gave ethylrac-(4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(1.7 g, 98%) as a colourless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55 -7.38 (m, 2H), 7.21 (ddt, J = 8.4, 4.1, 1.6 Hz, 1H), 4.20 - 3.98 (m, 2H),3.78 (q, J = 7.3 Hz, 1H), 1.63 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H), 1.02(d, J = 5.64 Hz, 3H) ppm. ESI-MS m/z calc. 350.0941, found 351.0 (M+1)⁺.

Step 2

Pd/C (10 wt. % loading, 456 mg, 0.43 mmol) was added to a solution ofethylrac-(4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(1.00 g, 2.86 mmol) in EtOH (50 mL) and the mixture vacuum degassed. Theflask was refilled with hydrogen and a balloon of hydrogen was bubbledthrough the solution over 5 mins. The reaction was stirred under aballoon of hydrogen at ambient temperature for 3 hours before theballoon was refreshed and the bubbling repeated. The reaction was thenleft stirring under a balloon of hydrogen for 3 days. The reactionmixture was filtered through celite and the filtrate dried in vacuo togive ethylrac-(2S,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1000 mg, 99%) as a colourless oil which crystallised on standing. ¹HNMR (500 MHz, Chloroform-d) δ 7.11 - 7.02 (m, 1H), 6.97 (dt, J = 10.0,8.2 Hz, 1H), 6.94 - 6.89 (m, 1H), 4.76 (d, J = 5.8 Hz, 1H), 3.96 (ttt, J= 10.8, 7.1, 3.8 Hz, 2H), 3.60 (dd, J = 8.5, 5.8 Hz, 1H), 2.71 (p, J =7.8 Hz, 1H), 1.50 - 1.40 (m, 3H), 0.89 (t, J = 7.1 Hz, 3H), 0.79 (dq, J= 7.6, 1.9 Hz, 3H) ppm.

Step 3

A solution of ethylrac-(2S,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.26 g, 3.58 mmol) and KOt-Bu (801 mg, 7.14 mmol) in tert-butanol (34mL) was stirred at ambient temperature for 16 hours. The reaction wasdiluted with EtOAc and acidified to pH 2 with 1 M HCl. The aqueous layerwas further extracted with EtOAc. The combined organic layers were dried(MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (1.22 g, 76%) as a pale yellow oil. ¹H NMR (500 MHz, Chloroform-d)δ 7.17 (dt, J = 10.0, 8.3 Hz, 1H), 7.07 (ddd, J = 11.3, 7.4, 2.3 Hz,1H), 6.97 (ddd, J = 8.5, 3.9, 1.8 Hz, 1H), 4.93 (d, J = 9.6 Hz, 1H),3.96 -3.86 (m, 1H), 2.64 (p, J = 7.7 Hz, 1H), 1.29 (s, 3H), 0.85 (dq, J= 7.4, 2.3 Hz, 3H) ppm. ESI-MS m/z calc. 324.0785, found 323.1 (M-1)⁻.

Step 4

Oxalyl chloride (28 µL, 0.32 mmol) was added to a solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (50 mg, 0.13 mmol) in DCM (1 mL) and DMF (5 µL, 0.065 mmol)stirring at 0° C., and the mixture was warmed to ambient temperatureover 30 min before being concentrated in vacuo. The residue wasazeotroped using toluene and the residue dissolved in DCM (1 mL). Tothis new solution was added DIPEA (46 µL, 0.26 mmol) and methyl4-aminopyridine-2-carboxylate (20.4 mg, 0.13 mmol) and the reactionstirred at ambient temperature for 1 hour. The reaction was quenched byaddition of MeOH and the mixture evaporated in vacuo. Purification byreverse phase preparative HPLC (basic eluent) gave methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(45 mg, 75%). ¹H NMR (500 MHz, Chloroform-d) δ 8.66 (d, J = 5.5 Hz, 1H),8.56 (s, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.95 (dd, J = 5.5, 2.2 Hz, 1H),7.20 (dt, J = 10.0, 8.3 Hz, 1H), 7.16 - 7.10 (m, 1H), 7.08 - 6.98 (m,1H), 5.00 (d, J = 10.4 Hz, 1H), 4.03 (s, 3H), 3.91 (dd, J = 10.3, 8.5Hz, 1H), 2.67 (p, J = 7.7 Hz, 1H), 1.71 (d, J = 1.1 Hz, 3H), 0.88 (dt, J= 7.3, 2.4 Hz, 3H) ppm; ¹⁹F NMR (471 MHz, Chloroform-d) δ -74.42,-136.68 (d, J = 21.4 Hz), -138.88 (d, J = 21.4 Hz) ppm. ESI-MS m/z calc.458.1265, found 459.2 (M+1)⁺.

Step 5

Methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(45 mg, 0.098 mmol) dissolved in methanolic ammonia (3 mL of 7 M, 21.00mmol) and MeOH (2.5 mL) and stirred at ambient temperature for 2.5hours. The reaction was heated at 50° C. for 1 hour 40 mins beforefurther methanolic ammonia (3 mL of 7 M, 21.00 mmol) was added. After afurther 20 mins the reaction was concentrated in vacuo. Purification bypreparative reverse phase HPLC (basic eluent) gaverac-(2R,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(15 mg). ESI-MS m/z calc. 443.12683, found 444.2 (M+1)⁺; 442.2 (M-1)⁻.

Step 6

rac-(2R,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamidewas separated by chiral SFC using a (R,R)-Whelk-O1 column, 5 µm particlesize, 25 cm x 21.2 mm from Regis Technologies to give two single isomersof unknown absolute configuration:

First Eluting Isomer (rt = 0.64 min):rel-(2S,3R,4R,5S)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(90, 2 mg, 5%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.63 (s, 1H), 8.49 (d, J =5.5 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 2.8 Hz, 1H), 7.84(dd, J = 5.5, 2.2 Hz, 1H), 7.71 - 7.55 (m, 1H), 7.48 (ddd, J = 12.3,7.8, 2.2 Hz, 1H), 7.42 (dt, J = 10.8, 8.6 Hz, 1H), 7.20 (d, J = 8.3 Hz,1H), 5.11 (d, J = 9.6 Hz, 1H), 4.18 (dd, J = 9.7, 7.6 Hz, 1H), 2.76 (p,J = 7.5 Hz, 1H), 1.62 (s, 3H), 0.83 - 0.64 (m, 3H) ppm. ESI-MS m/z calc.443.12683, found 444.2 (M+1)⁺; 442.2 (M-1)⁻.

Second Eluting Isomer (rt = 1.29 min):rel-(2R,3S,4S,5R)-4-[[3-(3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(91, 3 mg, 7%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.49 (d, J =5.5 Hz, 1H), 8.30 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.9 Hz, 1H), 7.84(dd, J = 5.5, 2.2 Hz, 1H), 7.60 (d, J = 2.9 Hz, 1H), 7.48 (ddd, J =12.1, 7.7, 1.8 Hz, 1H), 7.42 (dt, J = 10.7, 8.6 Hz, 1H), 7.20 (dd, J =9.5, 3.5 Hz, 1H), 5.12 (d, J = 9.7 Hz, 1H), 4.18 (dd, J = 9.7, 7.7 Hz,1H), 2.76 (p, J = 7.4 Hz, 1H), 1.62 (s, 3H), 0.75 (dd, J = 7.4, 2.4 Hz,3H) ppm. ESI-MS m/z calc. 443.12683, found 444.2 (M+1)⁺; 442.2 (M-1)⁻.

Example 16Rel-(2s,3r,4r,5,s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4-Ethyl-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(92) andRel-(2r,3s,4s,5r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4-Ethyl-5-Methyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(93)

Step 1

To a stirred solution of ethyl 2-diazo-3-oxo-hexanoate (5 g, 24.47 mmol)in DCM (50 mL) stirring at 0° C. was added TEA (6.5340 g, 9 mL, 64.57mmol). [Tert-butyl(dimethyl)silyl] trifluoromethanesulfonate (8.6250 g,7.5 mL, 32.63 mmol) was added very slowly and the reaction mixture wasstirred for 30 mins at 0° C. The reaction mixture was washed withsaturated aqueous NaHCO₃ solution (50 mL) and the organic layer dried(MgSO₄) and concentrated in vacuo to give ethyl(Z)-3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-hex-3-enoate (7 g, 96%)which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ5.16 (t, J = 7.3 Hz, 1H), 4.18 (q, J = 7.1 Hz, 4H), 2.04-2.11 (m, 3H),1.21 (t,J = 8 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 6H) ppm.

Step 2

To a stirred solution of 1,1,1-trifluoropropan-2-one (70 g, 624.72 mmol)in DCM (448 mL) stirring at -78° C. was added TiCl₄ (617 mL of 1 M,617.00 mmol) very slowly. A solution of ethyl(Z)-3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-hex-3-enoate (150 g, 452.33mmol) in DCM (152 mL, pre-dried over MgSO₄) was added and the reactionstirred for 1 hour at this temperature. The reaction mixture wasquenched with water (260 mL), the layers separated and the organic layerwashed with further water (200 mL), dried (MgSO₄) and concentrated invacuo to give ethylrac-(4R,5R)-2-diazo-4-ethyl-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate(66 g, 48%) as a light reddish liquid which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 6.17 (s,1H), 4.21-4.27(m,2H),4.1(d,J = 9.2 Hz,1H),1.77-1.82 (m,1H) 1.64-1.68 (m,1H), 1.29 (s, 3H),1.24 (t,J = 7 Hz,3H), 0.83 (t,J = 7.4 Hz,3H) ppm. ESI-MS m/z calc.296.0984, found 297.1 (M+1)⁺.

Step 3

To a stirred solution of rhodium(II) acetate (985 mg, 2.23 mmol) intoluene (340 mL) stirring at 100° C. was added a solution of ethylrac-(4R,5R)-2-diazo-4-ethyl-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate(66 g, 219.23 mmol) in toluene (1320 mL) slowly over 1 hour. Uponcomplete consumption of starting material the reaction mixture wasfiltered through celite and concentrated in vacuo to afford ethylrac-(4R,5R)-4-ethyl-5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(53 g, 86%) as a light yellow liquid which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 4.79 (s, 1H), 4.20-4.13 (m,2H), 2.95 (t, J = 4 Hz, 1H), 1.66 (s, 3H), 1.49 -1.41(m, 2H), 1.20 -1.14(m, 3H), 1.06 (t, J = 3.7 Hz, 3H) ppm.

Step 4

To a stirred solution of ethylrac-(4R,5R)-4-ethyl-5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(53 g, 187.71 mmol) in DCM (340 mL) stirring at 0° C. was added DIPEA(28.196 g, 38 mL, 218.16 mmol) followed by a solution oftrifluoromethanesulfonic anhydride (63.840 g, 38 mL, 226.27 mmol) in DCM(190 mL) dropwise over 20 mins. After addition the reaction was quenchedby addition of cool water and diluted in hexane. The organic layer waswashed with saturated aqueous sodium bicarbonate solution andconcentrated in vacuo. Purification by flash chromatography (SiO₂, 0 to1% EtOAc in hexane) gave ethylrac-(4R,5R)-4-ethyl-5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate(50 g, 65%). ¹H NMR (400 MHz, Chloroform-d) δ 4.36 (q, J = 7.1 Hz, 2H),3.01 (t, J = 6.9 Hz, 1H), 1.92 - 1.75 (m, J = 7.1 Hz, 2H),1.64 (s, 3H),1.35 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.5 Hz, 3H) ppm.

Step 5

To a stirred solution of (3,4-difluoro-2-methoxyphenyl) boronic acid (28g, 148.99 mmol) and ethylrac-(4R,5R)-4-ethyl-5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate(50 g, 122.41 mmol) in toluene (1000 mL) was added K₃PO₄ (188 mL of 2 M,376.00 mmol). The mixture was degassed with N₂ gas for 20 mins beforePd(PPh₃)₄ (7.2 g, 6.23 mmol) was added and the reaction heated to 100°C. for 1 hour. The reaction mixture was filtered through celite, thefiltrate was diluted with water (500 mL), and the aqueous layer wasextracted with EtOAc (2 × 750 mL). The combined organic layers weredried (MgSO₄) and concentrated in vacuo. Purification by flashchromatography (SiO₂, 0 to 2% EtOAc in hexane) gave ethylrac-(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(30.82 g, 62%) as a light yellow liquid. ¹H NMR (400 MHz, Chloroform-d)δ 6.91 - 6.76 (m, 2H), 4.12 (qq, J = 6.8, 3.6 Hz, 2H), 3.90 (d, J = 2.2Hz, 3H), 3.32 (t, J = 7.0 Hz, 1H), 1.72 (s, 3H), 1.63-1.68 (m, 1H), 1.46(dq, J = 14.6, 7.3 Hz, 1H), 1.11 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.4Hz, 3H) ppm. ESI-MS m/z calc. 394.1204, found 395.2 (M+1)⁺.

Step 6

To a solution of ethylrac-(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(30.8 g, 78.11 mmol) in DCM (275 mL) stirring at 0° C. was added BBr₃(100 mL of 1 M, 100.0 mmol) over 35 mins. The reaction mixture wasstirred at this temperature for 1 hour then quenched at this temperatureby the slow addition of a mixture of water (110 mL) and satutaredaqueous sodium bicarbonate solution (110 mL). The layers were separatedand the aqueous layer extracted with DCM (2 × 100 mL) and the combinedorganic extracts washed with water (100 mL), dried (MgSO₄), filtered andconcentrated in vacuo to give ethylrac-(4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(29.1 g, 98%) as an orangey-brown, powdery solid. ¹H NMR (500 MHz,Chloroform-d) δ 6.85 (ddd, J = 8.8, 5.7, 2.2 Hz, 1H), 6.77 (ddd, J =9.6, 8.8, 7.3 Hz, 1H), 5.87 (s, 1H), 4.30 - 4.12 (m, 2H), 3.44 - 3.33(m, 1H), 1.84 - 1.74 (m, 3H), 1.74 - 1.63 (m, 1H), 1.60 - 1.46 (m, 1H),1.21 (t, J = 7.1 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H) ppm. ESI-MS m/z calc.380.1047, found 381.2 (M+1)⁺; 379.0 (M-1)⁻.

Step 7

TFA (11.8 mL, 153.2 mmol) was added to a solution of ethylrac-(4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(29.1 g, 76.52 mmol) was dissolved in DCM (200 mL) stirring at ambienttemperature. The mixture was heated at 50° C. for 1 hour 45 mins beforebeing cooled to ambient temperature and quenched with saturated aqueoussodium bicarbonate solution (800 mL). The layers were separated, theaqueous layer extracted with DCM (3 × 200 mL), and the combined organicextracts dried (MgSO₄) and concentrated in vacuo. The residue wasre-dissolved in DCM (50 mL) and heptane (100 mL) was layered on top. Themixture was allowed to stand at ambient temperature overnight and theresultant solid isolated by filtration, washing with a minimum ofheptane. The filtrate was concentrated in vacuo, redissolved in DCM andheptane layered on top. The mixture was allowed to stand at ambienttemperature overnight and the resultant second crop of solid isolated byfiltration, washing with a minimum of heptane. The crops were combinedto giverac-(1S,2R)-1-ethyl-6,7-difluoro-2-methyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one(21.0 g, 82%) as a fluffy white solid. ¹H NMR (500 MHz, Chloroform-d) δ7.22 - 7.07 (m, 2H), 3.49 (dd, J = 7.3, 4.5 Hz, 1H), 2.16 - 1.92 (m,2H), 1.66 (q, J = 1.1 Hz, 3H), 1.06 - 0.96 (m, 3H) ppm; ¹⁹F NMR (471MHz, Chloroform-d) δ -74.15, -133.57 (d, J = 20.1 Hz), -153.89 (d, J =20.1 Hz) ppm. ESI-MS m/z calc. 334.06284, found 335.1 (M+1)⁺; 333.1(M-1)⁻.

Step 8

Pd(OH)₂ (27 g of 10 %w/w, 19.23 mmol) was added to a Parr vesselcontaining a solution ofrac-(1S,2R)-1-ethyl-6,7-difluoro-2-methyl-2-(trifluoromethyl)-1H-furo[2,3-c]chromen-4-one(21 g, 62.83 mmol) in MeOH (460 mL) that had first been left to sonicatefor 15 mins at 45° C. to get material into solution. The flask wasevacuated and refilled with H₂ three times before being shaken under 55psi of hydrogen for 24 h. The catalyst was removed by filtration throughcelite under a blanket of nitrogen, washing with EtOH. The filtrate wasconcentrated in vacuo to give methylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(16.2 g, 70%) as a fluffy white solid, in a mixture of diastereomers,also containing 5% of the acid side-product. ESI-MS m/z calc. 368.1047,found 368.9 (M+1)⁺; 367.2 (M-1)⁻.

Step 9

Methylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1000 mg, 2.616 mmol) was dissolved in ethanol (35 mL) and KOt-Bu (1.21g, 10.78 mmol) was added. The reaction mixture was stirred at ambienttemperature overnight before being concentrated in vacuo and the residuepartitioned between EtOAc and 1 M HCI. The layers were separated and theorganic layer passed through a phase separator cartridge andconcentrated in vacuo to giverac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (900 mg, 97%). ESI-MS m/z calc. 354.08905, found 356.3 (M+1)⁺.

Step 10

To a solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (1 g, 2.823 mmol) in acetonitrile (6 mL) was added K₂CO₃ (1.65 g,11.94 mmol) and MeI (1.6 g, 11.27 mmol). The mixture was heated in asealed vial at 80° C. for 6 hours before being diluted with DCM,filtered and the filtrate carefully concentrated in vacuo (cold waterbath). Purification by flash chromatography (24 g SiO₂, 10 to 55% EtOAcin heptane) gave methylrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(300 mg, 28%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.17 -7.08 (m, 2H), 5.13 (d,J = 6.1 Hz, 1H), 4.27 (dd, J = 8.7, 6.1 Hz, 1H), 3.89 (d, J = 1.5 Hz,3H), 3.36 (s, 3H), 2.75 (ddd, J = 10.5, 8.6, 4.2 Hz, 1H), 1.54 - 1.48(m, 3H), 1.52 - 1.36 (m, 1H), 0.73 (t, J = 7.3 Hz, 3H) ppm.

Step 11

To a solution of ethylrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(300 mg, 0.78 mmol) in EtOH (10 mL) was added KOt-Bu (363 mg, 3.24mmol). The reaction was stirred at ambient temperature overnight, thenconcentrated in vacuo. The residue was partitioned between EtOAc and 1 MHCI and the layers separated. The organic layer was passed through aphase separator cartridge and the filtrate evaporated in vacuo to giverac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (300 mg), which was used without any further purification. ¹H NMR(400 MHz, DMSO-d₆) δ 7.26-7.10 (m, 2H), 4.79 (d, J = 9.0 Hz, 1H), 4.17(t, J = 9.2 Hz, 1H), 3.92 (d, J = 1.9 Hz, 3H), 1.58-1.48 (m, 3H),1.45-1.31 (m, 1H), 1.30-1.02 (m, 2H), 0.50 (t, J = 7.3 Hz, 3H) ppm.

Step 12

To a solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (300 mg, 0.81 mmol) in DCM (15 mL) was added DMF (6.4 µL, 0.083mmol) and oxalyl chloride (216 µL, 2.48 mmol). The mixture was stirredat ambient temperature for 15 mins then concentrated in vacuo. Theresidue was diluted in DCM (3 mL) and added dropwise to a solution ofmethyl 4-aminobenzoate (185 mg, 1.22 mmol), DMAP (5 mg, 0.041 mmol) andNEt₃ (350 µL, 2.51 mmol) in DCM (5 mL) stirring at ambient temperature.The mixture was stirred for 16 hours then diluted in DCM (50 mL) andwashed with 2 M HCI (50 mL). The organic layers were passed through aphase separator cartridge and concentrated in vacuo to give methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(300 mg, 73%), which was used without further purification. ESI-MS m/zcalc. 502.1527, found 503.2 (M+1)⁺.

Step 13

Methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(300 mg, 0.5971 mmol) was dissolved in methanolic ammonia (500 mL of 2M, 1.00 mol). The reaction was stirred for 16 hours at ambienttemperature before being concentrated in vacuo. Purification by flashchromatography (24 g SiO₂, 0 to 100% EtOAc in heptane, loaded in DCM)gaverac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(116, 107.1 mg, 35%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 10.65(s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.06 (d, J= 2.5 Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H),7.25 - 7.16 (m, 2H), 4.94 (d, J = 8.8 Hz, 1H), 4.34 (t, J = 9.0 Hz, 1H),3.91 (d, J = 1.8 Hz, 3H), 2.63 - 2.60 (m, 1H), 1.63 (s, 3H), 1.47 - 1.41(m, 1H), 1.27 - 1.21 (m, 1H), 0.54 (t, J = 7.3 Hz, 3H) ppm; ¹⁹F NMR (471MHz, DMSO-d6) δ -72.26, -138.00 (d, J = 21.2 Hz), -154.96 (d, J = 21.2Hz) ppm. ESI-MS m/z calc. 487.15305, found 488.4 (M+1)⁺.

Step 14

rac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(245 mg, 0.480 mmol) was separated by chiral SFC using a (R,R)-Whelk-O1column, 5 µm particle size, 25 cm x 21.2 mm from Regis Technologies togive two single isomers of unknown absolute configuration:

First Eluting Isomer (rt = 0.96 min):rel-(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(92, 78.6 mg, 67%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.50 (dd,J = 5.5, 0.6 Hz, 1H), 8.28 (dd, J = 2.2, 0.6 Hz, 1H), 8.06 (d, J = 2.7Hz, 1H), 7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.62 - 7.61 (m, 1H), 7.25 -7.16 (m, 2H), 4.94 (d, J = 8.8 Hz, 1H), 4.34 (t, J = 9.1 Hz, 1H), 3.91(d, J = 1.8 Hz, 3H), 2.65 - 2.60 (m, 1H), 1.63 (s, 3H), 1.48 - 1.39 (m,1H), 1.28 - 1.19 (m, 1H), 0.54 (t, J = 7.3 Hz, 3H) ppm; ¹⁹F NMR (471MHz, DMSO-d₆) δ -72.26, -138.00 (d, J = 21.3 Hz), -154.96 (d, J = 21.4Hz) ppm. ESI-MS m/z calc. 487.15305, found 488.5 (M+1)⁺.

Second Eluting Isomer (rt = 2.07 min):rel-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4-ethyl-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(93, 87.5 mg, 74%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.65 (s, 1H), 8.50 (d,J = 5.6 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.1 Hz, 1H),7.82 (dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.9 Hz, 1H), 7.25 - 7.16(m, 2H), 4.94 (d, J = 8.8 Hz, 1H), 4.34 (t, J = 9.0 Hz, 1H), 3.91 (d, J= 1.8 Hz, 3H), 2.65 -2.60 (m, 1H), 1.63 (s, 3H), 1.48 - 1.40 (m, 1H),1.28 - 1.19 (m, 1H), 0.54 (t, J = 7.3 Hz, 3H) ppm; ¹⁹F NMR (471 MHz,DMSO-d₆) δ -72.26, -138.00 (d, J = 21.2 Hz), -154.96 (d, J = 21.4 Hz)ppm. ESI-MS m/z calc. 487.15305, found 488.8 (M+1)⁺.

The following compounds were made using a method similar to thatdescribed in Example 16, except that ethyl4-cyclopropyl-2-diazo-3-oxo-butanoate was used as the starting materialin place of ethyl 2-diazo-3-oxo-hexanoate in step 1. In step 8, 1 atm ofpressure of hydrogen was used rather than 55 psi. The conditions usedfor the saponification step 11 are similar to those used in Example 3step 10. In step 14, purification was performed by chiral SFC using aLux Cellulose-2 column, 5 µm particle size, 25 cm x 10 mm fromPhenomenex, Inc. to give two single isomers of unknown absoluteconfiguration:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 94rel-(2S,3R,4R,5S)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 499.15305,found 500.1 (M+1)⁺; 498.2 (M-1)⁻; Retention time: 3.32 minutes ¹H NMR(500 MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.27 (d, J= 2.1 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H),7.61 (s, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.20 - 7.11 (m, 1H), 5.14 (d, J= 10.4 Hz, 1H), 4.31 (first eluting peak by SFC on Lux Cellulose-2column, rt = 2.32 min) (dd, J = 10.3, 8.3 Hz, 1H), 3.92 (d, J = 1.9 Hz,3H), 1.88 (dd, J = 11.6, 8.2 Hz, 1H), 1.58 (s, 3H), 0.63 (s, 1H), 0.45(d, J = 13.7 Hz, 1H), 0.20 (q, J = 4.7 Hz, 1H), -0.04 - -0.17 (m, 1H),-0.48 (dd, J = 9.6, 5.0 Hz, 1H) ppm. 95rel-(2R,3S,4S,5R)-4-[[4-cyclopropyl-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 499.15305,found 500.6 (M+1)⁺; 498.7 (M-1)⁻; Retention time: 3.32 minutes ¹H NMR(500 MHz, DMSO-d₆) δ 10.77 (s, 1H), 8.58 (d, J = 5.5 Hz, 1H), 8.36 (d, J= 2.1 Hz, 1H), 8.14 (d, J = 2.8 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H),7.69 (d, J = 2.8 Hz, 1H), 7.32 (ddd, J = 8.1, 5.8, 1.8 Hz, 1H), 7.29 -7.20 (m, 1H), 5.23 (d, J = 10.4 Hz, 1H), 4.40 (dd, J = 10.4, 8.2 Hz,1H), 4.01 (d, J = 1.9 Hz, 3H), 1.96 (dd, J = 11.7, 8.3 Hz, 1H), 1.67 (s,3H), 0.71 (s, 1H), 0.51 (td, J = 8.6, 4.6 Hz, 1H), 0.28 (dt, J = 10.0,5.0 Hz, 1H), 0.06 - -0.06 (m, 1H), -0.40 (dd, J = 9.7, 4.9 Hz, 1H) ppm.(second eluting peak by SFC on Lux Cellulose-2 column, rt = 3.59 min)

Example 17 rel-(2R,3S,4R,5,S)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-(Difluoromethyl)-4,5-DimethylTetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(96), rel-(2S, 3R,4S, 5R)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-(Difluoromethyl)-4,5-Dimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(97), Rel-(2s,3r,4r,5,S)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-(Difluoromethyl)-4,5-Dimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(98) and rel-(2R,3S,4S,5R)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-(Difluoromethyl)-4,5-Dimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(99)

Step 1

To a solution of ethyl 2-diazo-3-oxo-pentanoate (30 g, 172.77 mmol) inDCM (300 mL) stirring at 0° C. was added Et₃N (45.999 g, 64 mL, 450.03mmol). TBSOTf (55.223 g, 49 mL, 204.73 mmol) was added slowly and themixture was stirred for 30 mins at the same temperature. The reactionmixture was diluted with 30% aqueous NaHCO₃ solution (200 mL), thelayers separated and the organic layer washed with water (500 mL), dried(MgSO₄) and concentrated in vacuo to give ethylrac-(Z)-3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-pent-3-enoate (48 g,98%), which was used without further purification.

Step 2

To a solution of 1,1-difluoropropan-2-one (14 g, 148.84 mmol) in DCM(100 mL) stirring at -78° C. was added dropwise TiCl₄ (28.545 g, 16.5mL, 150.49 mmol) and ethyl(Z)-3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-pent-3-enoate (20 g, 73.964mmol). The reaction was stirred at this temperature for 30 mins beforediluting in water. The layers were separated and the aqueous layerextracted with DCM (2 × 100 mL). The combined organic layers were washedwith water and brine, nad concentrated in vacuo. Purification by flashchromatography (SiO₂) gave ethylrac-(4R,5R)-2-diazo-6,6-difluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate(8.5 g, 43%) as a liquid. ¹H NMR (400 MHz, CDCl₃) δ 5.74 (t, J = 56.12Hz, 1H), 4.31(q, J = 14.24 Hz, 2H), 3.97-3.93 (m, 1H), 3.67 (s, 1H),1.34 (d, J = 7.16 Hz, 3H), 1.30 (s, 3H), 1.26-1.23 (m, 3H) ppm.

Step 3

A solution of rhodium(II) acetate (3 mg, 0.0068 mmol) in toluene wasstirred at 100° C. for 30 mins before a solution of ethylrac-(4R,5R)-2-diazo-6,6-difluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate(120 mg, 0.45 mmol) in toluene was added. The mixture was stirred at histemperature for 45 mins then cooled to ambient temperature and filtered.The filtrate was concentrated in vacuo to give ethylrac-(4R,5R)-5-(difluoromethyl)-4,5-dimethyl-3-oxo-tetrahydrofuran-2-carboxylate(90 mg, 84%) as a light brown liquid, which was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 5.66 (t, J = 54.62 Hz, 1H), 4.70(s, 1H), 4.30-4.22 (m, 2H), 2.54-2.46 (m, 1H), 1.71 (s, 3H), 1.38-1.28(m, 6H) ppm.

Step 4

Triflic anhydride (1.85 mL, 11.00 mmol) was added dropwise to a solutionof ethylrac-(4R,5R)-5-(difluoromethyl)-4,5-dimethyl-3-oxo-tetrahydrofuran-2-carboxylate(2000 mg, 8.47 mmol) and NEt₃ (3.55 mL, 25.47 mmol) in DCM (40 mL) withstirring at -78° C. After 2 hours, saturated aqueous NaHCO₃ was added,the layers separated and the aqueous layer extracted with DCM. Thecombined organic layers were passed through a phase separator cartridgeand concentrated in vacuo to give ethylrac-(4R,5R)-5-(difluoromethyl)-4,5-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate(3.8 g), containing some NEt₃, which was used as such in the next step,without any further purification. ESI-MS m/z calc. 368.0353, found 369.2(M+1)⁺.

Step 5

A mixture of ethylrac-(4R,5R)-5-(difluoromethyl)-4,5-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate(3250 mg, 8.83 mmol), (3,4-difluoro-2-methoxy-phenyl)boronic acid (2.0g, 10.64 mmol) and saturated aqueous NaHCO₃ (excess) in dioxane (80 mL)was degassed and refilled with nitrogen. Pd(PPh₃)₂Cl₂ (321 mg, 0.46mmol) was added and the mixture further degassed. The reaction washeated at 80° C. for 4 hours then cooled to ambient temperature andconcentrated in vacuo. The residue was disolved in EtOAc, washed withwater and brine, and the organic layer filtered through a Celite (10 g),washing with EtOAc, and concentrated in vacuo. Purification by flashchromatography (40 g SiO₂, 20 to 40% EtOAc in heptane, loaded in DCM)gave ethylrac-(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(difluoromethyl)-4,5-dimethyl-4,5-dihydrofuran-2-carboxylate(1.6 g, 50%) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.23 - 7.10 (m,1H), 7.10 -6.97 (m, 1H), 6.51 - 6.13 (m, 1H), 4.12 - 3.95 (m, 2H), 3.82(dd, J = 5.4, 1.8 Hz, 3H), 3.36 (m, 1H), 1.47 (d, J = 1.4 Hz, 3H),1.31 - 1.14 (m, 3H), 1.08 - 0.82 (m, 3H) ppm. ESI-MS m/z calc.362.11414, found 363.3 (M+1)⁺.

Step 6

EtOH (20 mL) was added to a flask containing ethylrac-(4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-(difluoromethyl)-4,5-dimethyl-4,5-dihydrofuran-2-carboxylate(300 mg, 0.83 mmol) and Pd/C (900 mg, 0.85 mmol). The mixture wasdegassed and then stirred under a balloon of hydrogen for 3 days. Thereaction mixture was filtered through Celite, washed with EtOH, and thefiltrate was concentrated in vacuo. To the residue was added Pd(OH)₂/C(20% wt, 1 equivalent) and EtOH (20 mL) and the mixture degassed andstirred under a balloon of hydrogen overnight. The mixture was filteredthrough Celite and the filtrate concentrated in vacuo to give a mixtureof isomers of ethyl3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carboxylate(300 mg, 99%). ESI-MS m/z calc. 364.12976, found 365.1 (M+1)⁺.

Step 7

To a solution of a mixture of isomers of ethyl3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carboxylate(300 mg, 0.82 mmol) in EtOH (10 mL) was added KOt-Bu (380 mg, 3.39mmol). The mixture was stirred at ambient temperature overnight thenconcentrated in vacuo. The residue was partitioned between EtOAc and 1 MHCI, the layers separated and the organic layer passed through a phaseseparator cartridge. The filtrate was concentrated in vacuo to give amixture of isomers of3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carboxylicacid (220 mg, 79%) as a colourless oil. ESI-MS m/z calc. 336.09848,found 335.1 (M-1)⁻.

Step 8 and 9

To a solution of a mixture of isomers of3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carboxylicacid (220 mg, 0.65 mmol) in DCM (6 mL) was added DMF (5 µL, 0.065 mmol)and oxalyl chloride (180 µL, 2.06 mmol). The reaction was stirred atambient temperature for 2 hours then concentrated in vacuo. The residuewas dissolved in DCM (3 mL) and added dropwise over 5 mins to a solutionof methyl 4-aminopyridine-2-carboxylate (150 mg, 0.99 mmol), DMAP (4 mg,0.033 mmol) and NEt₃ (280 µL, 2.01 mmol) in DCM (5 mL) stirring atambient temperature. The mixture was stirred overnight then evaporatedin vacuo. The residue was dissolved in methanolic ammonia (7 M, 5 mL)and the solution stirred at ambient temperature overnight before beingevaporated in vacuo. Purification by reverse phase preparative HPLC(basic eluent) gave two diastereomers ofrac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyltetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(100 mg total, 34%) in a 1:1 ratio. ESI-MS m/z calc. 455.14682, found456.1 (M+1)⁺; 454.1 (M-1)⁻.

Step 10

The two seperated diastereomers ofrac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(100 mg, 0.2196 mmol) were each further purified by chiral SFC using a(R,R)-Whelk-01 column, 5 µm particle size, 25 cm x 21.2 mm from RegisTechnologies to give single isomers of unknown absolute configuration:

First Eluting Isomer of Diastereoisomer 1 (rt = 4.45 min): rel-(2R, 3S,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(96, 16.9 mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.41 (d, J= 5.6 Hz, 1H), 7.98 (dd, J = 5.5, 2.1 Hz, 1H), 7.90 (d, J = 2.4 Hz, 2H),6.79 - 6.67 (m, 2H), 5.87 (s, 1H), 5.80 (t, 1H), 4.92 (d, J = 9.9 Hz,1H), 4.11 (s, 1H), 4.04 (d, J = 2.4 Hz, 3H), 2.55 (dq, J = 13.8, 7.1 Hz,1H), 1.65 (t, J = 1.6 Hz, 3H), 1.12 (dd, J = 7.0, 1.6 Hz, 3H) ppm.ESI-MS m/z calc. 455.14682, found 456.1 (M+1)⁺ ; 454.1 (M-1)⁻.

Second Eluting Isomer of Diastereoisomer 1 (rt = 5.00 min):rel-(2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(97, 16.5 mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.38 (d, J= 5.5 Hz, 1H), 8.03 (dd, J = 5.5, 2.2 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H),7.82 - 7.76 (m, 1H), 6.91 - 6.77 (m, 2H), 5.77 (t, J = 54.4 Hz, 1H),5.62 (d, J = 4.3 Hz, 1H), 4.62 (d, J = 9.7 Hz, 1H), 3.89 (d, J = 2.3 Hz,3H), 3.57 (ddd, J = 12.1, 9.7, 2.2 Hz, 1H), 2.38 (dqd, J = 14.3, 7.1,2.8 Hz, 1H), 1.42 (d, J = 1.7 Hz, 3H), 0.93 (dd, J = 7.2, 1.2 Hz, 3H)ppm. ESI-MS m/z calc. 455.14682, found 456.1 (M+1)⁺; 454.1 (M-1)⁻.

First Eluting Isomer of Diastereoisomer 2 (rt = 3.34 min):rel-(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(98, 17.8 mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 8.41 (d, J= 5.5 Hz, 1H), 7.98 (dd, J = 5.8, 2.1 Hz, 1H), 7.90 (d, J = 2.2 Hz, 2H),6.77 - 6.69 (m, 2H), 5.85 (d, J = 4.3 Hz, 1H), 5.80 (t, J = 54.5 Hz,1H), 4.92 (d, J = 10.0 Hz, 1H), 4.11 (t, J = 11.1 Hz, 1H), 4.03 (d, J =2.4 Hz, 3H), 2.55 (dq, J = 14.0, 7.1 Hz, 1H), 1.65 (t, J = 1.6 Hz, 3H),1.16 - 1.08 (m, 3H) ppm. ESI-MS m/z calc. 455.14682, found 456.1 (M+1)⁺;454.1 (M-1)⁻.

Second Eluting Isomer of Diastereoisomer 2 (rt = 4.00 min):rel-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(difluoromethyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(99, 18.1 mg). ¹H NMR (400 MHz, Chloroform-d) δ 8.81 (s, 1H), 8.47 (d, J= 5.5 Hz, 1H), 8.11 (dd, J = 5.5, 2.2 Hz, 1H), 7.99 (dd, J = 2.3, 0.6Hz, 1H), 7.87 (d, J = 4.4 Hz, 1H), 7.01 - 6.86 (m, 2H), 5.80 (t, J =54.3 Hz, 1H), 5.74 (s, 1H), 4.71 (d, J = 9.7 Hz, 1H), 3.98 (d, J = 2.3Hz, 3H), 3.66 (ddd, J = 12.1, 9.7, 2.2 Hz, 1H), 3.50 (s, 3H), 2.54 -2.40 (m, 1H), 1.02 (dd, J = 7.2, 1.1 Hz, 3H) ppm. ESI-MS m/z calc.455.14682, found 456.1 (M+1)⁺; 454.1 (M-1)⁻.

Example 18Rac-(2s,3s,4r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5,5-Trimethyl-Tetrahydrofuran-2-Carbonyl]amino]Pyridine-2-Carboxamide(100),Rel-(2s,3r,4s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5,5-Trimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(101) and Rel-(2r, 3s,4r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5,5-Trimethyl-Tetrahydrofuran-2-Carbonyl]Amino]pyridine-2-Carboxamide(102)

Step 1:

To a solution of acetone (5.3 mL, 71.54 mmol) in DCM (100 mL) stirringat -78° C. was added dropwise TiCl₄ (12.90 g, 7.5 mL, 68.01 mmol). Thereaction was stirred at this temperature for 10 mins before a solutionof ethyl (E)-3-[tert-butyl(dimethyl)silyl]oxy-2-diazo-pent-3-enoate (15g, 52.738 mmol) in DCM (100 mL) was added dropwise. The reaction wasstirred at -78° C. for 1 hour then quenched by addition of saturatedaqueous NaHCO₃. The mixture was diluted with DCM, the layers separatedand the organic layer dried (MgSO₄) and concentrated in vacuo.Purification by flash chromatography (SiO₂, 0 to 30% EtOAc in hexane)gave ethyl rac-2-diazo-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate as a paleyellow liquid. (3.6 g, 30%). ¹H NMR (400 MHz, Chloroform-d) δ 4.29 (q, J= 7.1 Hz, 2H), 3.69 (q, J = 7.0 Hz, 1H), 3.46 (br.s, 1H), 1.32 (t, J =7.1 Hz, 3H), 1.26 (s, 3H) 1.24 - 1.15 (m, 6H) ppm.

Step 2

A solution of rhodium (II) acetate (64 mg, 0.14 mmol) in toluene (36 mL)was heated at 100° C. for 10 minutes, then the heating removed and asolution of ethyl rac-2-diazo-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate(6.58 g, 28.83 mmol) in toluene (95 mL) was added dropwise. The reactionwas heated at reflux for 1 hour then filtered through Celite and thefiltrate concentrated in vacuo to give ethylrac-4,5,5-trimethyl-3-oxo-tetrahydrofuran-2-carboxylate, which was usedwithout further purification.

Step 3

To a solution of ethylrac-4,5,5-trimethyl-3-oxo-tetrahydrofuran-2-carboxylate (2.83 g, 14.13mmol) in DCM (5 mL) stirring at -78° C. was added DIPEA (3.1 mL, 17.80mmol). A solution of triflic anhydride (4.20 g, 2.5 mL, 14.89 mmol) inDCM (5 mL) was added dropwise over 20 mins. Upon complete addition thereaction was diluted with DCM and water, the layers separated and theorganic layer dried (MgSO₄) and concentrated in vacuo to give ethylrac-2,2,3-trimethyl-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(3.76 g, 80%) as a brown liquid. ¹H NMR (400 MHz, Chloroform-d) δ 4.33(q, J = 7.1 Hz, 2H), 2.93 (q, J = 7.1 Hz, 1H), 1.45 (s, 3H), 1.38 - 1.30(m, 6H), 1.14 (d, J = 7.1 Hz, 3H) ppm.

Step 4

To a solution of ethylrac-2,2,3-trimethyl-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate(3.1 g, 8.03 mmol) in toluene (19 mL) and EtOH (9.5 mL) was added(3,4-difluoro-2-methoxy-phenyl)boronic acid (2.1 g, 11.17 mmol) andK₃PO₄ (13 mL of 2 M, 26.00 mmol). The reaction was purged with argon for20 mins before[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (197 mg,0.24 mmol) was added and the mixture stirred at 100° C. for 16 hours.The reaction was concentrated in vacuo and the residue diluted in EtOAc(150 mL). The layers were separated and the organic layer wasconcentrated in vacuo. Purification by flash chromatography (SiO₂, 0 to50% EtOAc in hexane) gave ethylrac-4-(3,4-difluoro-2-methoxy-phenyl)-2,2,3-trimethyl-3H-furan-5-carboxylate(2.16 g, 82%) as a light yellow liquid. ¹H NMR (400 MHz, Chloroform-d) δ6.89 - 6.72 (m, 2H), 4.26 - 4.01 (m, 2H), 3.88 (d, J = 1.9 Hz, 3H), 3.07(q, J = 7.2 Hz, 1H), 1.49 (s, 3H), 1.36 (s, 3H), 1.10 (t, J = 7.2 Hz,3H), 0.89 (d, J = 7.2 Hz, 3H) ppm.

Step 5

A solution of ethylrac-4-(3,4-difluoro-2-methoxy-phenyl)-2,2,3-trimethyl-3H-furan-5-carboxylate(1 g, 3.06 mmol) in EtOH (40 mL) was degassed for 10 mins before Pd/C(500 mg, 4.70 mmol) was added. The reaction was stirred under a 250 psipressure of hydrogen for 16 hours, at ambient temperature, then filteredthrough Celite and the filtrate concentrated in vacuo. Purification byflash chromatography (SiO₂, 5% ethyl acetate in hexane) gave a mixtureof isomers of ethyl3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylate(700 mg, 70%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 6.84 -6.73 (m, 2H), 4.70 (d, J = 9.2 Hz, 1H), 4.03 (d, J = 2.3 Hz, 3H), 3.83-3.70 (m, 2H), 3.45 - 3.26 (m, 1H), 2.46 (q, J = 13.5 Hz, 1H), 1.51 (s,3H), 1.18 (s, 3H), 0.88 - 0.76 (m, 6H) ppm.

Step 6

To a solution of a mixture of isomers of ethyl3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylate(600 mg, 1.83 mmol) in THF (10 mL) stirring at 0° C. was added KOt-Bu(862 mg, 7.68 mmol). The reaction was stirred at this temperature for 9hours then quenched by addition of 2N HCl. The layers were separated andthe aqueous layer extracted with EtOAc and water. The organic layer wasdried (Na₂SO₄) and concentrated in vacuo. Purification by flashchromatography (SiO₂, 0 to 100% EtOAc in hexane) gave a mixture ofisomers of3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylicacid (390 mg, 71%).

Step 7

Oxalyl chloride (105 µL, 1.20 mmol) was added to a solution of a mixtureof isomers of3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylicacid (120 mg, 0.40 mmol) and DMF (5 µL, 0.065 mmol) in DCM (3 mL)stirring at 0° C. The mixture was warmed to ambient temperature over 30mins, then concentrated in vacuo. The residue was dissolved in DCM (2mL) and the solution cooled to 0° C. before methyl4-aminopyridine-2-carboxylate (100 mg, 0.66 mmol) and DIPEA (235 µL,1.35 mmol) were added. The reaction was stirred overnight, allowing towarm to ambient temperature, then quenched with water (20 mL) and thelayers separated. The aqueous layer was extracted with EtOAc (2 × 20 mL)and the combined organics layers were dried (MgSO₄), filtered andconcentrated in vacuo. Purification by flash chromatography (12 g SiO₂,0 to 15% MeOH in DCM) gave methyl4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(140 mg, 81%) as a colourless oil, containing an inseperable mixture ofdiastereomers. ESI-MS m/z calc. 434.1653, found 435.5 (M+1)⁺; 433.5(M-1)⁻.

Step 8 and 9

A solution of a mixture of diastereomers of methyl4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(140 mg, 0.32 mmol) in methanolic ammonia (9 mL of 7 M, 63.00 mmol) wasstirred at ambient temperature overnight, then concentrated in vacuo.Purification by flash chromatography (SiO₂, 0-10% MeOH in DCM) followedby reverse phase preparative HPLC (basic eluent) gave two diastereomers:

First Eluting minor diastereoisomer:rac-(2R,3R,4S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(100, 17 mg, 12%). ¹H NMR (500 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.31(d, J = 5.5 Hz, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.67 (d, J = 2.2 Hz,1H), 6.60 (dd, J = 9.0, 6.1 Hz, 2H), 5.58 (s, 1H), 4.57 (d, J = 10.1 Hz,1H), 3.98 (s, 3H), 3.85 (d, J = 11.0 Hz, 1H), 2.17 - 2.10 (m, 1H), 1.47(s, 3H), 1.18 (s, 3H), 0.83 (d, J = 6.8 Hz, 3H) ppm. ESI-MS m/z calc.419.16565, found 420.5 (M+1)⁺; 418.5 (M-1)⁻.

Second Eluting major diastereoisomer:rac-(2R,3S,4R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(62 mg, 46%). ¹H NMR (500 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.37 (d, J= 5.5 Hz, 1H), 8.12 (dd, J = 5.5, 2.2 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H),7.81 - 7.73 (m, 1H), 6.90 (ddd, J = 8.8, 5.7, 2.1 Hz, 1H), 6.85 (s, 1H),5.64 (s, 1H), 4.43 (d, J = 9.7 Hz, 1H), 3.91 - 3.84 (m, 3H), 3.47 (dd, J= 11.9, 9.7 Hz, 1H), 2.15 (dq, J = 11.9, 6.9 Hz, 1H), 1.37 (s, 3H), 1.20(s, 3H), 0.75 (d, J = 6.9 Hz, 3H) ppm.

The enantiomers of the major diasteromerrac-(2R,3S,4R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(62 mg, 0.15 mmol) were separated by chiral SFC using a Chiralpak AS-Hcolumn, 5um particle size, 25 cm x 10 mm from Daicel on a Minigram SFCinstrument from Berger Instruments to give two single isomers of unknownabsolute configuration:

First Eluting Isomer (rt = 2.09 min): rel-(2S,3R,4S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(101, 19 mg, 31%). ¹H NMR (500 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.37(d, J = 5.5 Hz, 1H), 8.12 (dd, J = 5.5, 2.2 Hz, 1H), 7.84 (d, J = 2.2Hz, 1H), 7.81 - 7.73 (m, 1H), 6.90 (ddd, J = 8.8, 5.7, 2.1 Hz, 1H), 6.85(s, 1H), 5.64 (s, 1H), 4.43 (d, J = 9.7 Hz, 1H), 3.91 - 3.84 (m, 3H),3.47 (dd, J = 11.9, 9.7 Hz, 1H), 2.15 (dq, J = 11.9, 6.9 Hz, 1H), 1.37(s, 3H), 1.20 (s, 3H), 0.75 (d, J = 6.9 Hz, 3H) ppm. ESI-MS m/z calc.419.16565, found 420.3 (M+1)⁺; 418.3 (M-1)⁻.

Second Eluting Isomer (rt = 2.87 min): rel-(2R,3S,4R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(102, 16 mg, 26%). ¹H NMR (500 MHz, Chloroform-d) δ 8.80 (s, 1H), 8.37(d, J = 5.5 Hz, 1H), 8.12 (dd, J = 5.5, 2.2 Hz, 1H), 7.84 (d, J = 2.2Hz, 1H), 7.81 - 7.73 (m, 1H), 6.90 (ddd, J = 8.8, 5.7, 2.1 Hz, 1H), 6.85(s, 1H), 5.64 (s, 1H), 4.43 (d, J = 9.7 Hz, 1H), 3.91 - 3.84 (m, 3H),3.47 (dd, J = 11.9, 9.7 Hz, 1H), 2.15 (dq, J = 11.9, 6.9 Hz, 1H), 1.37(s, 3H), 1.20 (s, 3H), 0.75 (d, J = 6.9 Hz, 3H) ppm. ESI-MS m/z calc.419.16565, found 420.3 (M+1)⁺; 418.3 (M-1)⁻.

Example 19Rel-(2r,3s,4r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5,5-Trimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(103),Rel-(2s,3r,4s)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5,5-Trimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(104),Rel-(2R,3S,4,S)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5,5-Trimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(105) andRel-(2s,3r,4r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5,5-Trimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(106)

Step 1

A solution of 3-hydroxy-3-methyl-butan-2-one (39 g, 381.86 mmol) anddimethyl propanedioate (25 g, 21.74 mL, 189.23 mmol) in MeOH (550 mL)was cooled to 0° C. and stirred under nitrogen. Cs₂CO₃ (127 g, 389.79mmol) was added and the mixture was stirred overnight. The reaction wasthen cooled to 0° C. and HCI (630 mL of 1 M, 630.00 mmol) was added. Thereaction mixture was concentrated to remove the MeOH, and then EtOAc(800 mL) was added and the layers were separated. The aqueous layer wasextracted with EtOAc (2 × 500 mL) and the combined organic layers dried(Na₂SO₄) and concentrated in vacuo. The residue was triturated withn-pentane to give 4,5,5-trimethyl-2-oxo-furan-3-carboxylic acid (29 g,90%) as a off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H),2.28 (s, 3H), 1.42 (s, 6H) ppm.

Step 2

4,5,5-trimethyl-2-oxo-furan-3-carboxylic acid (17 g, 99.904 mmol) washeated at 170° C.-180° C. for 4 hours then cooled to ambienttemperature. Purification by flash chromatography (SiO₂, 15% EtOAc inhexane) gave 4,5,5-trimethylfuran-2-one (10 g, 79%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 5.81 (s, 1H), 2.03 (s, 3H), 1.38 (s,6H) ppm. ESI-MS m/z calc. 126.0681, found 127.6 (M+1)⁺.

Step 3

A mixture of (1,5-cyclooctadine)(methoxy)iridium(I) dimer (1.2 g, 1.81mmol) and 4,4-di-tert-butyl-2,2′-bipyridine (1.6 g, 5.96 mmol) inn-heptane (50 mL) was degassed and stirred for 15 mins under nitrogen. Asolution of 4,5,5-trimethylfuran-2-one (15 g, 118.90 mmol) andbis(pinacolato)diboron (31.8 g, 125.23 mmol) in n-heptane (190 mL) wasdegassed and stirred under nitrogen for 5 mins and then added to thefirst solution. The resultant reaction mixture was heated at 80° C. for2 hours then cooled to ambient temperature. DIPEA (46.75 g, 63 mL,361.69 mmol) was added to a solution of1-bromo-3,4-difluoro-2-methoxy-benzene (39.8 g, 178.46 mmol) inTPGS-750-M (40.0 g, 40 mL of 2 %w/v, 69.59 mmol) and THF (240 mL) andthe mixture was degassed and stirred under nitrogen for 10 mins. Thiswas added to the cooled reaction mixture followed by PdCl₂(dtbpf) (3 g,4.60 mmol), and the resultant mixture was stirred overnight at ambienttemperature. The mixture was diluted with water (200 mL) and extractedwith EtOAc (2 × 700 mL).The combined organic layers were washed withbrine (200 mL), dried (Na₂SO₄) and concentrated in vacuo. Purificationby flash chromatography (SiO2, 3 to 5% EtOAc in hexane) gave3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-furan-2-one (19 g,58%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.25 - 7.23 (m, 1H),7.10-7.07 (m, 1H), 3.81 (d, J = 1.72 Hz, 3H), 1.93 (s, 3H), 1.49 (s, 6H)ppm. ESI-MS m/z calc. 268.0911, found 269.2 (M+1)⁺.

Step 4

To a solution of3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-furan-2-one (4.2 g,15.66 mmol) in MeOH (170 mL) and THF (34 mL) stirring at -40° C. wasadded NiCl₂.6H₂O (3.8 g, 15.99 mmol) and NaBH₄ (3 g, 79.30 mmol). Theresulting mixture was stirred for 5 mins before further NiCl₂.6H₂O (3.8g, 15.99 mmol) and NaBH₄ (3 g, 79.30 mmol) was added. Upon fullconversion the reaction was quenched by the addition of saturatedaqueous NH₄Cl and the aqueous layer extracted with DCM (2 × 50 mL). Thecombined organic extracts were dried (MgSO₄) and concentrated in vacuoto giverac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-one(3.72 g, 88%) as a 1:1.4 mixture of diasteromers. ESI-MS m/z calc.270.10675, found 271.4 (M+1)⁺.

Step 5

To a solution ofrac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-one(3.8 g, 14.06 mmol) in DCM (55 mL) stirring at -78° C. was added DIBAL(17 mL of 1 M, 17.00 mmol). The mixture was stirred at this temperatureuntil complete reaction was observed, then quenched by the addition ofsaturated ammonium chloride solution (20 mL) and Rochelle’s salt (30%w/w solution). The mixture was diluted with DCM (20 mL) and vigorouslystirred for 1 h at ambient temperaure. The layers were separated and theorganic layers dried (MgSO₄) and concentrated in vacuo to giverac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-ol(3.70 g, 97%), which was used without further purification.

Step 6

To a solution ofrac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-ol(3.7 g, 13.59 mmol) in DCM (40 mL) was added DMAP (850 mg, 6.96 mmol)and acetic anhydride (5.3 mL, 56.17 mmol). The reaction was stirred atambient temperature overnight then quenched by addition of saturatedaqueous sodium bicarbonate solution (50 mL). The mixture was stirredvigorously for 30 mins then the layers were separated. The aqueous layerwas extracted with DCM (20 mL) and the combined organic extracts weredried (MgSO₄) and concentrated in vacuo. Purification by flashchromatography (SiO₂) gaverac-[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-yl]acetate (3.0 g, 70%) as a mixture of stereoisomers. Data for desireddiastereomer: ¹H NMR (500 MHz, Chloroform-d) δ 6.91 (d, J = 1.4 Hz, 1H),6.86 - 6.76 (m, 2H), 3.91 (d, J = 1.7 Hz, 3H), 2.92 (qd, J = 7.0, 1.4Hz, 1H), 2.10 (s, 3H), 1.37 (s, 3H), 1.37 (s, 3H), 1.01 (d, J = 7.0 Hz,3H), 0.91 - 0.86 (m, 1H) ppm. ESI-MS m/z calc. 314.13297, found 256.6(M-OAc)⁺.

Step 7

To a solution ofrac-[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-yl]acetate (3 g, 9.544 mmol) in DCM (90 mL) stirring at -78° C. was addedtrimethylsilyl cyanide (3.3 mL, 24.75 mmol) anddiethyloxonio(trifluoro)boranuide (3.7 mL, 29.98 mmol) . The mixture wasstirred at this temperature for 30 mins then allowed to warm to ambienttemperature. Upon completion the mixture was quenched with saturatedaqueous sodium bicarbonate solution, the layers separated and theaqueous layer extracted with DCM (3 × 30 mL). The combined organiclayers were dried (Na₂SO₄) and concentrated in vacuo. The residue wasdissolved in DCM and filtered through Celite, then concentrated invacuo. NaOMe (30 mL of 0.5 M in methanol, 15.00 mmol) was added to theresidue and the resultant solution stirred at ambient temperatureovernight before being quenched by addition of a saturated solution ofcitric acid. The mixture was stirred at ambient temperature untilcomplete conversion of the amidate was observed, then extracted with DCM(2 × 30 mL). The combined organic layers were dried (MgS04) andconcentrated in vacuo to give methylrac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylate(900 mg, 30%), which was used in the next step without furtherpurification. ESI-MS m/z calc. 314.13297, found 315.6 (M+1)⁺.

Step 8

To a solution of methylrac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylate(440 mg, 1.40 mmol) in THF (5.4 mL) was added KOt-Bu (630 mg, 5.61 mmol)and the mixture stirred at ambient temperature. Upon completion, thereaction was quenched by addition of water and the aqueous layer washedwith DCM. The aqueous phase was acidified with 1 M HCI and extractedwith DCM. The organic layer was evaporated in vacuo to giverac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylicacid (420 mg, 100%) in a 1:1.4 ratio of diastereomers. ESI-MS m/z calc.300.1173, found 299.6 (M-1)⁻.

Step 9

To a solution ofrac-3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carboxylicacid (105 mg, 0.35 mmol) in DCM (1.2 mL) stirring at 0° C. was added DMF(3 µL, 0.039 mmol) and oxalyl chloride (65 µL, 0.75 mmol). The mixturewas warmed to ambient temperature over 30 mins then concentrated invacuo. The residue was dissolved in DCM (600 µL) and the resultantsolution added to a solution of methyl 4-aminopyridine-2-carboxylate (64mg, 0.42 mmol) and NEt₃ (68 µL, 0.49 mmol) in DCM (600 µL) stirring at0° C. The reaction was warmed to ambient temperature over 2 hours,quenched by addition of water (1 drop) and MeOH (2 mL), and the solutionconcentrated in vacuo. Purification by flash chromatography (SiO₂) gavemethylrac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(110 mg, 72%). ESI-MS m/z calc. 434.1653, found 435.5 (M+1)⁺; 433.6(M-1)⁻.

Step 10

Methylrac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(110 mg, 0.2532 mmol) was dissolved in methanolic ammonia (6 mL of 4 M,24.00 mmol) and the solution stirred at ambient temperature. Uponcomplete conversion the mixture was concentrated in vacuo to giverac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(100 mg, 94%) as a mixture of diasteromers. ESI-MS m/z calc. 419.16565,found 420.5 (M+1)⁺; 418.7 (M-1)⁻.

Step 11

rac-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(85 mg, 0.20 mmol) was separated by chiral SFC using a Lux i-Cellulose-5column, 5 µm particle size, 25 cm x 10 mm from Phenomenex, Inc. to give:

First Eluting Isomers (rt = 4.84 min): a mixture of bothrel-(2R,3S,4R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(103) andrel-(2S,3R,4,S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(104), that needed further separation.

Second Eluting Isomer (rt = 5.23 min):rel-(2R,3S,4S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(105, 10.2 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.46 (s, 1H), 8.47 (d, J =5.6 Hz, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.08 -8.05 (m, 1H), 7.87 (dd, J =5.5, 2.2 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.22 - 7.11 (m, 2H), 4.87 (d, J =8.5 Hz, 1H), 4.22 (t, J = 8.1 Hz, 1H), 3.91 (d, J = 1.8 Hz, 3H), 2.35(p, J = 7.4 Hz, 1H), 1.40 (s, 3H), 1.20 (s, 3H), 0.59 (d, J = 7.3 Hz,3H) ppm. ESI-MS m/z calc. 419.16565, found 420.6 (M+1)⁺; 418.5 (M-1)⁻.

Third Eluting Isomer (rt = 5.67 min):rel-(2S,3R,4R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(106, 14.4 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.32 (broad s, 1H), 8.47(d, J = 5.5 Hz, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 2.7 Hz, 1H),7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.58 (d, J = 2.9 Hz, 1H), 7.26 - 7.11(m, 2H), 4.87 (d, J = 8.6 Hz, 1H), 4.22 (t, J = 8.1 Hz, 1H), 3.91 (d, J= 1.8 Hz, 3H), 2.35 (p, J = 7.3 Hz, 1H), 1.40 (s, 3H), 1.20 (s, 3H),0.59 (d, J = 7.3 Hz, 3H) ppm. ESI-MS m/z calc. 419.16565, found 420.6(M+1)⁺; 418.6 (M-1)⁻.

The first eluting peak was further separated by chiral SFC using aChiralpak AS-H column, 5 µm particle size, 25 cm x 10 mm from Daicel ona Minigram SFC instrument from Berger Instruments:

First Eluting Isomer (rt = 2.27 min):rel-(2R,3S,4R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(103, 6 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.24 (s, 1H), 8.47 (d, J = 5.6Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 7.87 (dd, J = 5.5, 2.2Hz, 1H), 7.65 - 7.61 (m, 1H), 7.26 (ddd, J = 8.3, 5.9, 1.9 Hz, 1H), 7.18(td, J = 9.4, 7.5 Hz, 1H), 4.53 - 4.44 (m, 1H), 3.83 (d, J = 1.4 Hz,3H), 3.70 - 3.59 (m, 1H), 2.19 (dq, J = 11.8, 6.8 Hz, 1H), 1.37 (s, 3H),1.20 (s, 3H), 0.78 (d, J = 6.8 Hz, 3H) ppm. ESI-MS m/z calc. 419.16565,found 420.6 (M+1)⁺; 418.5 (M-1)⁻.

Second Eluting Isomer (rt = 3.22 min):rel-(2S,3R,4S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5,5-trimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(104, 5.4 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 10.19 (s, 1H), 8.46 (dd, J =5.7, 1.7 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.04 (s, 1H), 7.86 (dt, J =5.7, 1.9 Hz, 1H), 7.58 (s, 1H), 7.26 (dd, J = 8.6, 6.2 Hz, 1H), 7.23 -7.14 (m, 1H), 4.46 (dd, J = 9.4, 1.6 Hz, 1H), 3.83 (d, J = 1.5 Hz, 3H),3.63 (ddd, J = 11.2, 9.3, 1.7 Hz, 1H), 2.19 (dtd, J = 12.6, 7.6, 5.9 Hz,1H), 1.37 (d, J = 1.7 Hz, 3H), 1.20 (d, J = 1.7 Hz, 3H), 0.77 (dd, J =6.9, 1.7 Hz, 3H) ppm. ESI-MS m/z calc. 419.16565, found 420.6 (M+1)⁺;418.5 (M-1)⁻.

Example 20Rel-(2s,3r,4r,5r)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5-Dimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(107) andRel-(2r,3s,4s,5,s)-4-[[3-(3,4-Difluoro-2-MethoxyPhenyl)-4,5-Dimethyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(108)

Step 1

To a solution of 4,5-dimethylfuran-2-carboxylic acid (1 g, 7.14 mmol) inTHF (15 mL) stirring at -78° C. was added n-BuLi (6.56 mL of 2.5 M,16.40 mmol) dropwise. The solution was stirred at this temperature for30 mins before a solution of I₂ (2.35 g, 9.26 mmol) in THF (10 mL) wasadded. The mixture was warmed to ambient temperature then partitionedbetween MTBE (30 mL) and water (30 mL). The organic layer was discarded,and the aqueous layer acidified to pH 2 by addition of 1 N HCl andextracted with MTBE (2 × 20 mL). The combined organic layers were washedwith brine (10 mL), dried (MgSO₄) and concentrated in vacuo to give3-iodo-4,5-dimethyl-furan-2-carboxylic acid (950 mg, 48%), which wasused without further purification. ESI-MS m/z calc. 265.944, found 265.3(M-1)⁻.

Step 2

To a solution of 3-iodo-4,5-dimethyl-furan-2-carboxylic acid (900 mg,3.38 mmol) in DMF (5 mL) was added K₂CO₃ (1.40 g, 10.13 mmol) andiodoethane (811 µL, 10.14 mmol). The reaction was stirred at 50° C. for2 hours before being cooled to ambient temperature and partitionedbetween MTBE (30 mL) and water (30 mL). The aqueous layer was furtherextracted with MTBE (20 mL) and the combined organic fractions werewashed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo.Purification by flash chromatography (12 g SiO₂, 0 to 100% EtOAc inpetroleum ether) gave ethyl 3-iodo-4,5-dimethyl-furan-2-carboxylate (800mg, 71%) as a white solid. ESI-MS m/z calc. 293.97528, found 295.3(M+1)⁺.

Step 3

To a solution of ethyl 3-iodo-4,5-dimethyl-furan-2-carboxylate (700 mg,2.38 mmol) in dioxane (6 mL) was added(3,4-difluoro-2-methoxy-phenyl)boronic acid (492 mg, 2.62 mmol),Pd(PPh₃)₄ (343 mg, 0.30 mmol), Na₂CO₃ (3.57 mL of 2 M, 7.14 mmol) andwater (2 mL). The mixture was heated to 80° C. for 2 hours then cooledto ambient temperature and partitioned between EtOAc (30 mL) and water(30 mL). The aqueous layer was further extracted with EtOAc (50 mL) andcombined organic layers were washed with brine (20 mL), dried (MgSO₄)and concentrated in vacuo. Purification by flash chromatography (12 gSiO₂, 0 to 100% EtOAc in petroleum ether) gave ethyl3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-furan-2-carboxylate (520mg, 70%) as a white solid. ¹H NMR (500 MHz, Chloroform-d) δ 6.97 - 6.82(m, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.81 (d, J = 2.0 Hz, 3H), 2.37 (d, J= 0.8 Hz, 3H), 1.80 (d, J = 0.8 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H) ppm.ESI-MS m/z calc. 310.10165, found 311.4 (M+1)⁺.

Step 4

A solution of ethyl3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-furan-2-carboxylate (350mg, 1.128 mmol) in ethanol (2 mL) was circulated through a 70 mm Pd(OH)₂catalyst cartridge on an H-cube apparatus at 60° C. under 60 barpressure of hydrogen for 48 hours before being concentrated in vacuo togive ethylrac-(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyltetrahydrofuran-2-carboxylate(245 mg, 62%). ¹H NMR (500 MHz, Chloroform-d) δ 7.19 - 7.08 (m, 1H),6.72 (td, J = 9.3, 7.6 Hz, 1H), 4.55 (d, J = 6.1 Hz, 1H), 4.25 (dq, J =9.1, 6.6 Hz, 1H), 4.19 - 4.02 (m, 1H), 4.02 - 3.81 (m, 5H), 2.79 (ddt, J= 16.4, 8.9, 7.4 Hz, 1H), 1.27 - 1.04 (m, 3H), 0.86 (t, J = 7.1 Hz, 3H),0.55 (d, J = 7.4 Hz, 3H) ppm. ESI-MS m/z calc. 314.13297, found 315.4(M+1)⁺.

Step 5

To a solution of ethylrac-(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carboxylate(400 mg, 1.27 mmol) in THF (5 mL) stirring at 0° C. was added KOt-Bu(428 mg, 3.81 mmol). The reaction was stirred for 30 mins before beingdiluted in MTBE (5 mL) and quenched by addition of 1 M HCl. The aqueouslayer was extracted with MTBE (5 mL) and the combined organic layerswere dried (MgSO₄), filtered and concentrated in vacuo to giverac-(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carboxylicacid (270 mg, 66%) as an oil. ESI-MS m/z calc. 286.10165, found 285.4(M-1)⁻.

Step 6

To a solution ofrac-(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyltetrahydrofuran-2-carboxylicacid (100 mg, 0.3493 mmol) in MeCN (2 mL) was added methyl4-aminopyridine-2-carboxylate (63 mg, 0.41 mmol), 1-methylimidazole (100µL, 1.26 mmol) and TCFH (117 mg, 0.42 mmol). The solution was stirred atambient temperature for 16 hours then diluted with EtOAc (10 mL) andwater (10 mL). The organic layer was dried (MgSO₄) and concentrated invacuo to give methylrac-(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(95 mg, 65%) as a white solid, which was used without furtherpurification. ESI-MS m/z calc. 420.1497, found 421.5 (M+1)⁺.

Step 7 and 8

To a solution of methylrac-(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(95 mg, 0.23 mmol) in MeOH (1 mL) was added methanolic ammonia (322 µLof 7 M, 2.25 mmol). The mixture was stirred at ambient temperature for 6hours before being concentrated in vacuo to giverac-(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide.

rac-(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamidewas separated by chiral SFC using a Chiralpak AS-H column, 5 um particlesize, 25 cm x 10 mm from Daicel on a Minigram SFC instrument from BergerInstruments:

First Eluting Isomer (rt = 1.84 min):rel-(2S,3R,4R,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(107, 28 mg, 29%). ¹H NMR (500 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.48(d, J = 5.5 Hz, 1H), 8.23 (dd, J = 5.6, 2.3 Hz, 1H), 7.95 (d, J = 2.2Hz, 1H), 7.89 (s, 1H), 7.12-7.09 (m,1H), 7.02 - 6.83 (m, 1H), 5.58 (s,1H), 4.86 (d, J = 9.7 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.10 - 3.84 (m, 4H),2.56 (dt, J = 13.5, 6.8 Hz, 1H), 1.35 (d, J = 6.4 Hz, 3H), 0.67 (d, J =7.2 Hz, 3H) ppm. ESI-MS m/z calc. 405.15002, found 406.3 (M+1)⁺.

Second Eluting Isomer (rt = 3.28 min):rel-(2R,3S,4S,5S)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(108, 28 mg, 30%). ¹H NMR (500 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.48(d, J = 5.5 Hz, 1H), 8.23 (dd, J = 5.6, 2.3 Hz, 1H), 7.95 (d, J = 2.2Hz, 1H), 7.89 (s, 1H), 7.12-7.09 (m,1H), 7.02 - 6.83 (m, 1H), 5.58 (s,1H), 4.86 (d, J = 9.7 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.10 - 3.84 (m, 4H),2.56 (dt, J = 13.5, 6.8 Hz, 1H), 1.35 (d, J = 6.4 Hz, 3H), 0.67 (d, J =7.2 Hz, 3H) ppm. ESI-MS m/z calc. 405.15002, found 406.3 (M+1)⁺.

Example 21Rel-(25,3r,55)-4-[[3-(3,4-Difluoro-2-Methoxy-Phenyl)-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(109) andRel-(2r,3s,5r)-4-[[3-(3,4-Difluoro-2-MethoxyPhenyl)-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(110)

Step 1

To a solution of diisopropylamine (2.3 mL, 16.41 mmol) in THF (15 mL)stirring at -78° C. was added butyllithium (6 mL of 2.5 M, 15.00 mmol),keeping the temperature below -65° C. The reaction mixture was stirredat -75° C. for 30 mins before a solution of 3-bromofuran (2 g, 13.61mmol) in THF (10 mL) was added dropwise, again keeping the temperaturebelow -65° C. The mixture was stirred at -78° C. for 30 mins beforebeing added slowly to a pre-cooled (to -78° C.) mixture of dry ice (600mg, 13.63 mmol) and MTBE (25 mL). Further dry ice was added during theaddition. The mixture was allowed to warm to ambient temperature over 2hours before being carefully added to water (50 mL). The layers wereseparated and the aqueous phase extracted with MTBE (× 2). The aqueousphase was acidified to pH 3 with 1 M HCl and again extracted with MTBE(× 3). The combined organic extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo to give 3-bromofuran-2-carboxylic acid (2.17 g,83%) as a white solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 1.9Hz, 1H), 6.66 (d, J = 1.8 Hz, 1H) ppm.

Step 2

To a solution of 3-bromofuran-2-carboxylic acid (2.17 g, 11.36 mmol) inDMF (25 mL) was added potassium carbonate (4.7 g, 34.01 mmol) andethyliodide (2.7 mL, 33.76 mmol). The reaction mixture was heated to 65°C. for 40 mins then allowed to cool and stirred over the weekend. Thereaction mixture was filtered, washing with EtOAc and then the filtratediluted with water. The layers were separated and the aqueous layerextracted with EtOAc. The combined organic layers were washed with water(× 5) then dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was dissolved in EtOAc and adsorbed onto diatomaceous earth(Telos nm). Purification by flash chromatography (24 g SiO₂, 0 to 50%EtOAc in heptane) gave ethyl 3-bromofuran-2-carboxylate (1.8322 g, 74%)as a white solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.50 (d, J = 1.9 Hz,1H), 6.60 (d, J = 1.8 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J =7.1 Hz, 3H) ppm.

Step 3

A mixture of ethyl 3-bromofuran-2-carboxylate (1.55 g, 7.08 mmol),(3,4-difluoro-2-methoxy-phenyl)boronic acid (1.45 g, 7.72 mmol),Pd(PPh₃)Cl₂ (98 mg, 0.14 mmol) and NaHCO₃ (5 mL) in dioxane (20 mL) washeated at 50° C. for 1 hour before being cooled to ambient temperatureand diluted with EtOAc and water. The layers were separated and theaqueous phase was extracted with EtOAc (4 ×). The combined organicextracts were washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was dissolved in EtOAc and adsorbedonto diatomaceous earth (Telos nm). Purification by flash chromatography(24 g SiO₂, 0 to 20% EtOAc in heptane) gave ethyl3-(3,4-difluoro-2-methoxy-phenyl)furan-2-carboxylate (1.5105 g, 76%) asa clear oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 1.7 Hz, 1H),7.07 (ddd, J = 8.8, 5.9, 2.3 Hz, 1H), 6.90 (ddd, J = 9.6, 8.8, 7.3 Hz,1H), 6.57 (d, J = 1.8 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.82 (d, J =2.0 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z calc. 282.07037,found 283.4 (M+1)⁺.

Step 4

To a solution of ethyl3-(3,4-difluoro-2-methoxy-phenyl)furan-2-carboxylate (200 mg, 0.71 mmol)in DCE (25 mL) was added tris(2,2′-bipyridyl)dichlororuthenium(II)hexahydrate (11 mg, 0.015 mmol). The reaction mixture was degassed withnitrogen and pyridine (172 µL, 2.13 mmol) was added followed bytrifluoromethylsulfonyl trifluoromethanesulfonate (358 µL, 2.13 mmol)dropwise over 10 mins. The mixture was irradiated with blue LEDs (PennPhD photoreactor M2 and the Blue LED Hepatochem) for 2 hours stirring atambient temperature (100 rpm). This process was repeated 13 times, andthe crude mixtures combined for work up. The combined mixture was washedwith water and brine and the organic layer dried (MgSO₄) andconcentrated in vacuo. Purification by flash chromatography (24 g SiO₂,0 to 20% EtOAc in heptane) gave ethyl3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)furan-2-carboxylate(2.39 g, 72%) as a clear oil that solidifies on standing. ¹H NMR (500MHz, Chloroform-d) δ 7.07 (ddd, J = 8.8, 5.8, 2.3 Hz, 1H), 6.97 - 6.87(m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 3.88 (d, J = 2.5 Hz, 3H), 1.28 (t, J= 7.1 Hz, 3H) ppm. ESI-MS m/z calc. 350.05774, found 351.4 (M+1)⁺.

Step 5

A solution of ethyl3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)furan-2-carboxylate(2.29 g, 6.538 mmol) in ethanol (200 mL) was added to Pd(OH)₂/C (920 mgof 20 %w/w, 1.310 mmol) and the mixture degassed with nitrogen. Themixture is stirred under a balloon pressure of hydrogen for 18 hoursbefore further Pd(OH)₂ (920 mg of 20 %w/w, 1.310 mmol) was added, themixture degassed with nitrogen and then stirred under a balloon pressureof hydrogen for 18 hours. The mixture was filtered through celite,washing with ethanol, and the filtrate concentrated in vacuo to giveethylrac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(3.2 g, 95%). ¹H NMR (500 MHz, Chloroform-d) δ 6.91 - 6.75 (m, 2H), 4.88(d, J = 8.8 Hz, 1H), 4.49 (dp, J = 11.9, 6.0 Hz, 1H), 4.15 - 4.03 (m,4H), 3.88 - 3.70 (m, 2H), 2.66 (td, J = 12.5, 10.7 Hz, 1H), 2.31 (dt, J= 11.9, 5.9 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/z calc.354.08905, found 355.0 (M+1)⁺.

Step 6

To a solution of ethylrac-(2S,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(3.2 g, 6.233 mmol) in MeOH (100 mL) was added cesium carbonate (4 g,12.28 mmol). The mixture was heated at 50° C. for 16 hours before beingconcentrated in vacuo. The residue was partitioned between EtOAc and 1 MHC1, the layers separated and the organic layer passed through a phaseseparator and concentrated in vacuo to giverac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (1.9947 g, 98%) as a yellow oil. ¹H NMR (500 MHz, Chloroform-d) δ6.96 (ddd, J = 8.8, 5.5, 2.2 Hz, 1H), 6.88 (td, J = 9.1, 7.2 Hz, 1H),4.70 - 4.59 (m, 2H), 4.00 (d, J = 2.7 Hz, 3H), 3.92 - 3.78 (m, 1H),2.68 - 2.54 (m, 1H), 2.35 -2.25 (m, 1H) ppm. ESI-MS m/z calc. 326.05774,found 325.0 (M-1)⁻.

Step 7

To a solution ofrac-(2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (80 mg, 0.25 mmol) in MeCN (3 mL) was added methyl4-aminopyridine-2-carboxylate (44 mg, 0.29 mmol). 1-methylimidazole (70mg, 0.8526 mmol) and TCFH (82 mg, 0.29 mmol) were added and the reactionstirred at ambient temperature for 16 hours. The reaction mixture waspartitioned between EtOAc (10 mL) and water (10 mL), the layersseparated and the aqeuous layer further extracted with EtOAc (10 mL).The combined organic layers were washed with brine (10 mL), dried(MgSO₄) and concentrated in vacuo to give methylrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(70 mg, 36%), which was used without further purification. ESI-MS m/zcalc. 460.10577, found 461.6 (M+1)⁺.

Step 8 and 9

To a solution of methylrac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(50 mg, 0.11 mmol) in MeOH (1 mL) was added methanolic ammonia (155 µLof 7 M, 1.1 mmol) and the mixture stirred at ambient temperatureovernight before being concentrated in vacuo to giverac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide.

rac-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamidewas separated by chiral SFC using a (R,R)-Whelk-O1 column, 5 um particlesize, 25 cm x 21.2 mm from Regis Technologies to give two singleenantiomers of unknown absolute configuration:

First Eluting Isomer (rt = 0.75 min):rel-(2S,3R,5S)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(109, 5 mg, 10%). ¹H NMR (500 MHz, Chloroform-d) δ 8.57 (s, 1H), 8.50(d, J = 5.6 Hz, 1H), 8.13 (dd, J = 5.5, 2.3 Hz, 1H), 8.00 (d, J = 2.2Hz, 1H), 7.84 (s, 1H), 7.11 - 7.00 (m, 1H), 6.99 - 6.84 (m, 1H), 5.56(s, 1H), 4.76 (d, J = 10.2 Hz, 1H), 4.73 - 4.56 (m, 1H), 4.02 (d, J =2.6 Hz, 3H), 3.83 (q, J = 10.4 Hz, 1H), 2.70 (dt, J = 13.0, 7.7 Hz, 1H),2.42 (td, J = 12.1, 8.8 Hz, 1H) ppm. ESI-MS m/z calc. 445.1061, found446.5 (M+1)⁺.

Second Eluting Isomer (rt = 1.15 min):rel-(2R,3S,5R)-4-[[3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(110, 5 mg, 10%). ¹H NMR (500 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.50(d, J = 5.5 Hz, 1H), 8.13 (dd, J = 5.5, 2.2 Hz, 1H), 8.00 (d, J = 2.5Hz, 1H), 7.84 (s, 1H), 7.03 (t, J = 6.4 Hz, 1H), 6.93 (q, J = 8.8 Hz,1H), 5.56 (s, 1H), 4.76 (d, J = 10.2 Hz, 1H), 4.69 (q, J = 7.3 Hz, 1H),4.02 (d, J = 2.6 Hz, 3H), 3.91 - 3.70 (m, 1H), 2.70 (dt, J = 13.0, 7.7Hz, 1H), 2.42 (td, J = 12.2, 8.8 Hz, 1H) ppm. ESI-MS m/z calc. 445.1061,found 446.5 (M+1)⁺.

The following compounds were made using the method described in Example21, except that (4-fluoro-2-methoxy-3-methyl-phenyl)boronic acid wasused as coupling partner in the Suzuki coupling step 3 and theconditions used for the amide formation step 7 are similar to those usedin Example 14 step 4:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 111rel-(2S,3R,5S)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (first eluting isomer by SFCon (R,R)-Whelk-01 column, rt = 0.82 min) ESI-MS m/z calc. 441.13116,found 442.5 (M+1)⁺; 440.6 (M-1)⁻; Retention time: 2.95 minutes 112rel-(2R,3S,5R)-4-[[3-(4-fluoro-2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (second eluting isomer by SFCon (R,R)-Whelk-O1 column, rt = 1.38 min) ESI-MS m/z calc. 441.13116,found 442.3 (M+1)⁺; 440.3 (M-1)⁻; Retention time: 2.96 minutes ¹H NMR(500 MHz, DMSO-d₆) δ 10.53 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.26 (d, J= 2.2 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.83 (dd, J = 5.5, 2.2 Hz, 1H),7.60 (d, J = 2.8 Hz, 1H), 7.31 (dd, J = 8.7, 6.5 Hz, 1H), 7.02 (t, J =8.8 Hz, 1H), 5.03 - 4.91 (m, 1H), 4.59 (d, J = 9.4 Hz, 1H), 4.05 - 3.95(m, 1H), 3.59 (s, 3H), 2.77 (dt, J = 12.5, 7.4 Hz, 1H), 2.16 - 2.04 (m,4H) ppm.

Example 224-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-Methoxy-Phenyl)-5-Isopropyl-4-Methyl-Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(113)

Step 1

To a solution of (4R)-4-benzyloxazolidin-2-one (29.7 g, 164.26 mmol) inTHF (297 mL) cooled to -65° C. was added n-BuLi (65.7 mL of 2.5 M, 164.2mmol) dropwise, keeping the temperature at -65° C. The resulting mixturewas stirred at -65° C. for 30 min before propanoyl chloride (17.059 g,16.247 mL, 180.69 mmol) was added dropwise. The mixture was stirred at-65° C. for 1 hour and then allowed to warm to ambient temperatureovernight. The mixture was quenched by addition of saturated aqueousNH₄Cl solution (300 mL) and the aqueous layer extracted with EtOAc (2 ×300 mL). The combined organic layers were washed with saturated aqueousNaHCO₃ solution (300 mL) and brine (200 mL), dried (MgSO₄), filtered andevaporated in vacuo to give (4R)-4-benzyl-3-propanoyl-oxazolidin-2-one(39 g, 100%) as a colorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 7.46 -7.14 (m, 5H), 4.69 (ddt, J = 9.5, 6.9, 3.4 Hz, 1H), 4.27 - 4.15 (m, 2H),3.32 (dd, J = 13.4, 3.3 Hz, 1H), 2.98 (qd, J = 7.3, 5.9 Hz, 2H), 2.80(dd, J = 13.4, 9.6 Hz, 1H), 1.23 (t, J = 7.4 Hz, 3H) ppm. ESI-MS m/zcalc. mass 233.105, found, 233.95 [M+1]⁺.

Step 2

To a solution of (4R)-4-benzyl-3-propanoyl-oxazolidin-2-one (13.12 g,56.25 mmol) in DCM (130 mL) cooled to 0° C. was added titaniumtetrachloride (59 mL of 1 M in DCM, 59.00 mmol). The resulting mixturewas stirred at 0° C. for 15 mins before DIPEA (8.1620 g, 11 mL, 63.15mmol) was added and the mixture stirred at this temperature for 40 mins.NMP (5.5512 g, 5.4 mL, 55.999 mmol) was added and the reaction stirredfor 10 mins at ambient temperature before isobutyraldehyde (4.2660 g,5.4 mL, 59.16 mmol) was added and the mixture was stirred at 0° C. for 1hour and then at ambient temperature overnight. The mixture was quenchedwith a mixture of water (50 mL) and saturated aqueous NH₄Cl solution (50mL) and extracted with DCM (3 × 100 mL). The combined organic extractswere dried (Na₂SO₄), filtered and concentrated in vacuo. Purification byflash chromatography (SiO₂, 0 to 20% EtOAc to hexane) gave(4R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2,4-dimethyl-pentanoyl]oxazolidin-2-one(16 g, 86%) as a light yellow oil. ¹H NMR (300 MHz, Chloroform-d) δ7.44 - 7.16 (m, 5H), 4.72 (ddt, J = 9.4, 6.9, 3.3 Hz, 1H), 4.30 - 4.17(m, 2H), 3.99 (qd, J = 7.0, 2.6 Hz, 1H), 3.56 (dd, J = 8.6, 2.6 Hz, 1H),3.28 (dd, J = 13.4, 3.4 Hz, 1H), 2.90 (d, J = 3.4 Hz, 1H), 2.81 (dd, J =13.4, 9.4 Hz, 1H), 1.75 (dp, J = 8.5, 6.6 Hz, 1H), 1.27 (d, J = 7.0 Hz,3H), 1.06 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H) ppm. ESI-MS m/zcalc. 305.1627, found 306.05 (M+1)⁺.

Step 3

To a solution of(4R)-4-benzyl-3-[(2R,35)-3-hydroxy-2,4-dimethyl-pentanoyl]oxazolidin-2-one(100 g, 301.27 mmol) in MeOH (750 mL) stirring at 0° C. was added sodiummethoxide (19.609 g, 83 mL of 25%w/w in methanol, 90.74 mmol). Themixture was stirred for 30 mins at ambient temperature before beingquenched with saturated aqueous NH₄Cl solution (300 mL) and the aqueouslayer extrated with DCM (3 × 200 mL). The combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo. Purification byflash column chromatography (SiO₂, 10 to 20% diethyl ether in hexane)gave methyl (2R,3S)-3-hydroxy-2,4-dimethyl-pentanoate (40.24 g, 73%) asa colorless liquid, containing 12% hexane by weight. ¹H NMR (300 MHz,Chloroform-d) δ 3.73 (s, 3H), 3.59 (dt, J = 7.9, 3.9 Hz, 1H), 2.70 (qd,J = 7.2, 3.6 Hz, 1H), 2.45 (dd, J = 4.1, 1.8 Hz, 1H), 1.69 (ddd, J =13.3, 8.0, 6.7 Hz, 1H), 1.21 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.6 Hz,3H), 0.90 (d, J = 6.8 Hz, 3H) ppm.

Step 4

To a solution of diisopropylamine (67.146 g, 93 mL, 663.56 mmol) in THF(1 L) cooled to -65° C. was added n-BuLi (228 mL of 2.5 M in hexanes,570 mmol). The mixture was stirred for 30 mins at -65° C. before asolution of tert-butyl acetate (66.143 g, 77 mL, 569.42 mmol) in THF(100 mL) was added dropwise followed by solution of methyl(2R,3S)-3-hydroxy-2,4-dimethyl-pentanoate (40 g, 189.75 mmol) in THF(100 mL). The mixture was stirred for 1 hour at -50° C. and then allowedto warm to ambient temperature overnight. The reaction was quenched byaddition of ice-water (800 mL) and extracted with DCM (3 × 400 mL). Thecombined organic layers were washed with saturated NaHCO₃ (500 mL),water (2 × 500 mL), dried (Na₂SO₄), filtered and evaporated in vacuo.Purification by reverse phase flash chromatography (SiO₂ C18,acetonitrile/water 0 to 60%) gave tert-butyl(4R,5S)-5-hydroxy-4,6-dimethyl-3-oxo-heptanoate (7.95 g, 16%) as ayellow oil. ¹H NMR (300 MHz, Chloroform-d) δ 3.62 (dt, J = 8.7, 3.2 Hz,1H), 3.54 - 3.39 (m, 2H), 2.88 (qd, J = 7.2, 2.8 Hz, 1H), 2.57 (d, J =3.7 Hz, 1H), 1.71 (ddt, J = 13.3, 8.6, 6.7 Hz, 1H), 1.49 (s, 9H), 1.17(d, J = 7.2 Hz, 3H), 1.05 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H)ppm.

Step 5

To a solution of N-(4-azidosulfonylphenyl)acetamide (10.33 g, 43.00mmol) in acetonitrile (160 mL) was added tert-butyl(4R,5S)-5-hydroxy-4,6-dimethyl-3-oxo-heptanoate (7.9 g, 30.72 mmol). Themixture was cooled to 0° C. and triethylamine (9.29 g, 12.8 mL, 91.84mmol) was added. The reaction mixture was warmed to ambient temperatureand stirred overnight before being concentrated. Purification by flashchromatography gave tert-butyl(4R,5S)-2-diazo-5-hydroxy-4,6-dimethyl-3-oxo-heptanoate (7.58 g, 89%) asa yellow oil. ¹H NMR (300 MHz, Chloroform-d) δ 3.78 (qd, J = 7.1, 2.5Hz, 1H), 3.54 (dt, J = 8.6, 2.7 Hz, 1H), 3.10 (d, J = 2.8 Hz, 1H),1.81 - 1.66 (m, 1H), 1.55 (s, 9H), 1.16 (d, J = 7.1 Hz, 3H), 1.05 (d, J= 6.6 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H) ppm. ESI-MS m/z calc. 270.158,found 271.1 (M+1)⁺.

Step 6

To a suspension of rhodium (II) acetate (134 mg, 0.30 mmol) in toluene(25 mL) stirring at 60° C. was added a solution of tert-butyl(4R,5S)-2-diazo-5-hydroxy-4,6-dimethyl-3-oxo-heptanoate (8.63 g, 30.33mmol) in toluene (78 mL). The mixture was stirred at 60° C. for 1 hour,then cooled to ambient temperature, filtered through filter paper andconcentrated in vacuo to give tert-butyl(4R,5S)-5-isopropyl-4-methyl-3-oxo-tetrahydrofuran-2-carboxylate (7.34g, 90%) as a light yellow oil.

Step 7

To a solution of tert-butyl(4R,5S)-5-isopropyl-4-methyl-3-oxo-tetrahydrofuran-2-carboxylate (500mg, 2.06 mmol) in DCM (15 mL) stirring at a cooled -65° C. was addedDIPEA (1.1 mL, 6.32 mmol) and trifluoromethylsulfonyltrifluoromethanesulfonate (0.45 mL, 2.67 mmol). The reaction mixture wasstirred for 2 hours at -65° C. before further trifluoromethylsulfonyltrifluoromethanesulfonate (0.45 mL, 2.66 mmol) was added. The mixturewas stirred at -60° C. for 1 hour and then further DIPEA (0.4 mL, 2.30mmol) and trifluoromethylsulfonyl trifluoromethanesulfonate (0.45 mL,2.66 mmol) were added and the mixture was stirred for 1 hour at -60° C.and 1 hour at -40° C. The mixture was quenched with saturated aqueousNaHCO₃ solution (15 mL) and the aqueous layer extracted with DCM (3 × 10mL). The combined organic layers were dried (MgSO₄), filtered andevaporated in vacuo. The residue was dissolved in EtOAc (30 mL) andwashed with 1 M HCl (3 × 30 mL). The organic layer was dried (Na₂SO₄),filtered and concentrated in vacuo to give tert-butyl(2S,3R)-2-isopropyl-3-methyl-4-(trifluoromethylsulfonyloxy)-2,3-dihydrofuran-5-carboxylate(676 mg, 88%) as a brown oil, which was used without furtherpurification.

Step 8

A mixture of crude tert-butyl(2S,3R)-2-isopropyl-3-methyl-4-(trifluoromethylsulfonyloxy)-2,3-dihydrofuran-5-carboxylate(676 mg, 1.81 mmol),2-(3,4-difluoro-2-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(731 mg, 2.71 mmol) and sodium carbonate (478 mg, 4.51 mmol) in dioxane(13.5 mL) and water (3.5 mL) in a pressure glass reactor was degassed bybubbling argon through it for 15 mins. Next Pd(dppf)Cl₂.DCM (206 mg,0.2523 mmol) was added and the reactor was sealed. The reaction mixturewas stirred at 80° C. overnight before being cooled to ambienttemperature, diluted with EtOAc (20 mL), filtered through celite andconcentrated in vacuo. Purification by flash chromatography gavetert-butyl(2S,3S)-4-(3,4-difluoro-2-methoxy-phenyl)-2-isopropyl-3-methyl-2,3-dihydrofuran-5-carboxylate(107 mg, 14%) as a yellow oil. ¹H NMR (300 MHz, Chloroform-d) δ 6.98 -6.74 (m, 2H), 4.14 (dd, J = 10.2, 8.0 Hz, 1H), 3.92 (d, J = 1.8 Hz, 3H),3.18 - 2.99 (m, 1H), 2.14 (dp, J = 10.1, 6.4 Hz, 1H), 1.30 (s, 9H), 1.19(d, J = 6.5 Hz, 3H), 0.97 (dd, J = 7.8, 6.8 Hz, 6H) ppm; ¹⁹F NMR (376MHz, Chloroform-d) δ -136.92 - -137.21 (m), -155.04 - -155.40 (m) ppm.

Step 9

Ethanol (3.5 mL) was added to a mixture of tert-butyl(2S,3S)-4-(3,4-difluoro-2-methoxy-phenyl)-2-isopropyl-3-methyl-2,3-dihydrofuran-5-carboxylate(118 mg, 0.32 mmol) and Pd/C (Degussa, wet, 350 mg, 0.33 mmol). Themixture was degassed and stirred under a balloon of hydrogen for 4 daysbefore being filtered through celite, washing with EtOAc. The filtratewas concentrated in vacuo to give tert-butyl(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carboxylate(100 mg, 84%). ¹H NMR (400 MHz, Chloroform-d) δ 7.11 - 7.03 (m, 1H),6.83 - 6.75 (m, 1H), 4.45 (d, J = 7.9 Hz, 1H), 4.23 (t, J = 8.3 Hz, 1H),3.93 (d, J = 1.5 Hz, 3H), 3.49 (dd, J = 9.9, 6.9 Hz, 1H), 2.76 - 2.63(m, 1H), 1.97 - 1.83 (m, 1H), 1.15 (s, 9H), 1.13 (d, J = 6.5 Hz, 3H),0.90 (d, J = 6.5 Hz, 3H), 0.70 (d, J = 7.4 Hz, 3H) ppm.

Step 10

Tert-butyl(2S,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carboxylate(100 mg, 0.27 mmol) and potassium tert-butoxide (60 mg, 0.53 mmol) weremixed in tert-butanol (2.6 mL) and stirred at ambient temperature. After1 hour the reaction was heated to 35° C. After 2 hours at thistemperature the reaction was cooled to ambient temperature, LiOH (400 µLof 2 M, 0.80 mmol) was added and the reaction stirred at ambienttemperature for 16 h. The reaction was diluted with EtOAc and quenchedwith 1 M aqueous HCl. The aqueous layer was separated and extracted withEtOAc. The combined organic layers were dried (MgSO₄), filtered andconcentrated in vacuo to afford(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carboxylicacid (100 mg) as a white solid, which was used without furtherpurification.

Step 11

To a solution of(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carboxylicacid (100 mg, 0.3181 mmol) in DCM (3 mL) stirring at 0° C. was added DMF(5 µL, 0.065 mmol) and oxalyl chloride (90 µL, 1.03 mmol). After 30 minsthe reaction mixture was concentrated in vacuo. The residue was dilutedin DCM (2 mL) and the solution added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (75 mg, 0.4929 mmol) and Et₃N (300 µL,2.15 mmol) in DCM (1.5 mL) stirring at 0° C. DMAP (5 mg, 0.041 mmol) wasadded and the reaction stirred at this temperature for 10 mins beforebeing warmed to ambient temperature and stirred for 16 h. The reactionmixture was diluted with DCM and washed with 1 M HCl solution, theorganic layer dried (MgSO₄), filtered and concentrated in vacuo directlyonto silica. Purification by flash chromatography (24 g SiO₂, 0 to 100%EtOAc in petrol) gave methyl4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(73 mg, 51%). ESI-MS m/z calc. 448.18097, found 449.2 (M+1)⁺; 447.3(M-1)⁻.

Step 12

Methyl4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(73 mg, 0.1628 mmol) was stirred in methanolic ammonia (5 mL of 7 M,35.00 mmol) at ambient temperature overnight. The reaction mixture wasconcentrated in vacuo and purified by chiral SFC using a Chiralpak AS-Hcolumn (5 µm particle size, 25 cm × 10 mm from Daicel) on a Minigram SFCinstrument from Berger Instruments to remove a minor diastereomer togive4-[[(2R,3S,4S,5S)-3-(3,4-difluoro-2-methoxy-phenyl)-5-isopropyl-4-methyl-tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(113, 30.5 mg, 41%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.47 (d,1H), 8.25 (d, J = 2.2 Hz, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.85 (dd, J =5.5, 2.2 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.25 - 7.10 (m, 2H), 4.87(d, J = 10.1 Hz, 1H), 4.09 (dd, J = 10.2, 5.8 Hz, 1H), 3.95 - 3.84 (m,4H), 3.29 (s, 1H), 1.78 - 1.61 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H), 0.86(d, J = 6.6 Hz, 3H), 0.58 (d, J = 7.0 Hz, 3H) ppm. ESI-MS m/z calc.433.1813, found 434.2 (M+1)⁺; 432.3 (M-1)⁻.

Example 236-[[(2R,3S,4S,5R)-3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(114)

Step 1

rac-(1S,2R)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one(1348 g, 4.366 mol) was separated by chiral SFC using a (R,R)-Whelk-O1column, 5 µm particle size, 15 cm x 3 cm from Regis Technologies on aMultiGram III SFC instrument from Berger Instruments to give:

First Eluting Isomer (rt = 1.85 min):(1R,2S)-6,7-difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one(only an analytical sample was collected). ¹H NMR (400 MHz, DMSO-d₆) δ7.57 (ddd, J = 9.0, 5.5, 2.0 Hz, 1H), 7.51 (ddd, J = 10.3, 9.0, 7.0 Hz,1H), 4.03 (q, J = 7.2 Hz, 1H), 1.65 (s, 3H), 1.45 (dt, J = 6.9, 2.2 Hz,3H) ppm. ESI-MS m/z calc. 320.04718, found 321.3 (M+1)⁺; 319.4 (M-1)⁻.

Second Eluting Isomer (rt = 2.38 min):(1S,2R)-6,7-Difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one(366.99 g, 26%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.57 (ddd, J = 9.0, 5.5,2.0 Hz, 1H), 7.50 (ddd, J = 10.3, 9.0, 7.0 Hz, 1H), 4.03 (q, J = 7.2 Hz,1H), 1.65 (s, 3H), 1.45 (dt, J = 6.9, 2.2 Hz, 3H) ppm. ESI-MS m/z calc.320.04518, found 321.4 (M+1)⁺; 319.4 (M-1)⁻.

Step 2

A solution of(1S,2R)-6,7-Difluoro-1,2-dimethyl-2-(trifluoromethyl)-1,2-dihydro-4H-furo[2,3-c]chromen-4-one(0.89 kg, 2.78 mol) and 20% palladium hydroxide on carbon (50% wet, 0.39kg, 0.278 mol) in MeOH (12 L) was stirred under a 40 psi pressure ofhydrogen overnight. An increase in the reaction temperature to 37° C.was observed after reacting overnight and the mixture was cooled to 24°C. and hydrogenation was continued for a total of 48 hours. The mixturewas filtered through celite, washing with MeOH (20 L) and the filtratewas concentrated in vacuo. The residue was dissolved in toluene (4 L)and concentrated in vacuo, and this process repeated. The residue wasdried under vacuum at 40° C. overnight to give methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.0 kg at 91% purity, 100%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆)10.20 (br s, 1H), 6.94 (br t, J = 7.4 Hz, 1H), 6.79-6.69 (m, 1H), 5.10(d, J = 6.0 Hz, 1H), 4.20 (dd, J = 6.1, 8.2 Hz, 1H), 3.43 (s, 3H), 2.94(quin, J = 7.7 Hz, 1H), 1.46 (s, 3H), 0.77 (br d, J = 6.8 Hz, 3H) ppm.

Step 3

Potassium carbonate (2.0 kg, 14.4 mol) and iodomethane (800 mL, 12.8mol) were sequentially added to a solution of methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.0 kg, 2.82 mol) in acetonitrile (10 L) under nitrogen stirring atambient temperature. After stirring overnight, additional iodomethane(120 mL, 2 mmol) was added. After stirring overnight, additionaliodomethane (60 mL, 0.85 mmol) was added and the mixture was stirred for3 days. The reaction mixture was diluted with MTBE (30 L), treated withcelite (1 kg) and filtered through a bed of celite (1 kg) washing withMTBE (10 L). The filtrate was filtered a second time through celite (1kg) washing with MTBE (4 L) and the filtrate concentrated in vacuo. Theresidue was dissolved in toluene (4 L) and concentrated in vacuo, andthis process repeated. The residue was dried under vacuum at 40° C.overnight to give methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(0.99 kg at 90% purity, 95%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆)7.14-7.00 (m, 2H), 5.14 (d, J = 6.0 Hz, 1H), 4.15 (dd, J = 6.2, 8.4 Hz,1H), 3.88 (d, J = 1.7 Hz, 3H), 2.97 (quin, J = 7.8 Hz, 1H), 1.48 (s,3H), 0.72 (br d, J = 6.6 Hz, 3H) ppm.

Step 4 and 5

Sodium methoxide (25% in methanol, 65 mL, 0.28 mol) was added to asolution of methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.98 kg, 2.66 mol) in THF (10 L) stirringat ambient temperature under nitrogen. After 5 hours, MeOH (1 L), water(1 L) and lithium hydroxide monohydrate (0.168 kg, 4.0 mol) weresequentially added and the mixture was stirred overnight. The reactionmixture was poured into 1 M HCl (4.4 L, 4.4 mol) then extracted withMTBE (20 L). The aqueous layer was further extracted with MTBE (2 × 5 L)and the combined organic layers washed with brine (2 L), dried (Na₂SO₄)then treated with activated carbon (50 g, 5% w/w) with stirring for 1 h.The mixture was filtered through celite, washing with MTBE (2 × 4 L) andthe filtrate concentrated in vacuo. The residue was dissolved in toluene(4 L) and concentrated in vacuo, then dissolved in MTBE (4 L) andconcentrated in vacuo again to give(2R,35,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (1.06 kg at 77.7% purity) as an amber oil, which was used withoutfurther purification.

Step 6

Crude(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (2.09 kg at 77% purity, 4.54 mol) was dissolved in MTBE (25 L) in a100 L Chemglass reactor then stirred at 84 rpm at ambient temperature. Amixture of (R)-1-phenylethylamine (0.704 kg, 5.81 mol) and MTBE (2 L)was added to the reactor, followed by additional MTBE to give a totalvolume of 30 L in the reactor. After 2 hours additional MTBE (2 L) wasadded to the reaction and after a total of 3.5 hours the mixture wasfiltered, washing with MTBE (2 L). The reactor was rinsed with MTBE (4L), which was used to rinse the solids, which were then compressed anddried on the Büchner funnel for 2 hours. The solid product cake wasloosened then dried under a stream of nitrogen and under vacuumovernight on the Büchner funnel. The isolated solids were dried in aconvection oven at 40° C. for 24 hours to give(2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (R)-1-phenylethan-1-amine salt (1.86 kg at 95.7% purity, 74% over 3steps) as an off-white solid. ¹H NMR, 400 MHz, DMSO-d₆) 8.34 (br s, 2H),7.46-7.41 (m, 2H), 7.36-7.27 (m, 3H), 7.16-7.11 (m, 1H), 7.10-7.03 (m,1H), 4.58 (d, J = 9.9 Hz, 1H), 4.23 (q, J = 6.7 Hz, 1H), 3.99 (dd, J =7.8, 9.8 Hz, 1H), 3.90 (d, J = 2.0 Hz, 3H), 2.60 (quin, J = 7.5 Hz, 1H),1.50 (s, 3H), 1.40 (d, J = 6.7 Hz, 3H), 0.71-0.59 (m, 3H) ppm.

Step 7

To a suspension of(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (1R)-1-phenylethanamine salt (10.6 g, 22.29 mmol) in MTBE (250 mL)was added HCl (200 mL of 2 M, 400.0 mmol). The layers were separated andthe organic layer was washed with water (200 mL), dried (MgSO₄),filtered and concentrated in vacuo to give(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (8.4 g, 99%) as an oil. ¹H NMR (400 MHz, Chloroform-d) δ 6.96 (ddd,J = 7.9, 5.6, 2.0 Hz, 1H), 6.88 (td, J = 9.2, 7.3 Hz, 1H), 4.96 (d, J =10.5 Hz, 1H), 4.15 (dd, J = 10.5, 8.0 Hz, 1H), 4.02 (d, J = 2.8 Hz, 3H),2.74 (p, J = 7.6 Hz, 1H), 1.64 (t, J = 1.2 Hz, 3H), 0.79 (dq, J = 7.4,2.3 Hz, 3H) ppm.

Step 8

To an ice cooled solution of(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (63 mg, 0.1672 mmol) in 2-methyltetrahydrofuran (0.6 mL) was addedDMF (1.8880 mg, 2 µL, 0.0258 mmol) followed by carefully addition ofoxalyl chloride (37.830 mg, 26 µL, 0.2980 mmol). The reaction mixturewas warmed up to room temperature and stirred for 1 hr. The reactionmixture was concentrated in vacuo and the residue dissolved in2-methyltetrahydrofuran (0.6 mL). To this was added methyl6-aminopyridine-2-carboxylate (25 mg, 0.1643 mmol) and triethylamine(34.122 mg, 47 µL, 0.3372 mmol). The resulting mixture was stirred atroom temperature for 1 hour. The reaction mixture was quenched withwater (5 mL) and partitioned with ethyl acetate (10 mL). The layers wereseparated and the organic phase was washed with brine (5 mL), dried(sodium sulfate), filtered and concentrated under reduced pressure.Purification by flash chromatography (Biotage Isolera, 12 g SiliaSep 25µm Silicycle flash cartridge, 0 to 100% ethyl acetate in heptane) gavemethyl6-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(72 mg, 83%) as a pale yellow glassy oil. ¹H NMR (400 MHz, Chloroform-d)δ 9.04 (s, 1H), 8.37 (dd, J = 8.2, 1.1 Hz, 1H), 7.87 (dd, J = 7.6, 0.9Hz, 1H), 7.84-7.75 (m, 1H), 7.09-7.04 (m, 1H), 6.88 (td, J = 9.2, 7.5Hz, 1H), 5.00 (d, J = 11.0 Hz, 1H), 4.12-4.06 (m, 1H), 3.99 (d, J = 3.4Hz, 3H), 3.97 (d, J = 3.0 Hz, 3H), 2.76-2.68 (m, 1H), 1.69 (s, 3H),0.82-0.69 (m, 3H) ppm. ESI-MS m/z calc. 488.1371, found 489.14 (M+1)⁺.

Step 9

A solution of methyl6-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(72 mg, 0.1388 mmol) in ammonia (7 M in methanol) (1 mL of 7 M, 7.0000mmol) was stirred at room temperature overnight and then concentrated invacuo to give a colourless oil. Purification by flash chromatography(Biotage Isolera, 12 g SiliaSepC18 Monomeric 25 µm Silicycle flashcartridge, 30 to 90% acetonitrile containing 0.1% ammonium hydroxide inwater containing 0.1% ammonium hydroxide). Fractions containing productwere freeze dried to give6-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(114, 24.5 mg, 36%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ8.85 (s, 1H), 8.31 (dd, J = 8.2, 0.7 Hz, 1H), 7.97 (dd, J = 7.6, 0.7 Hz,1H), 7.84 (t, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.12-7.08 (m, 1H), 6.90(td, J = 9.2, 7.5 Hz, 1H), 5.62 (s, 1H), 5.03 (d, J = 11.0 Hz, 1H), 4.11(dd, J = 10.9, 8.1 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H), 2.79-2.70 (m, 1H),1.71 (s, 3H), 0.81-0.78 (m, 3H) ppm. ESI-MS m/z calc. 473.1374, found474.15 (M+1)⁺.

The following compounds were made using the method described in Example23, except that different coupling partners were used in the amidecoupling step 8:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1176-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrazine-2-carboxamide ESI-MS m/z calc. 474.1326,found 475.48 (M+1)⁺; Retention time: 2.4 minutes ¹H NMR (400 MHz,Chloroform-d) δ 9.64 (s, 1H), 9.17 (d, J = 0.5 Hz, 1H), 8.85 (s, 1H),7.39 (s, 1H), 7.10-7.04 (m, 1H), 6.92 (td, J = 9.2, 7.4 Hz, 1H), 5.70(s, 1H), 5.07 (d, J = 11.0 Hz, 1H), 4.13 (dd, J = 11.0, 8.2 Hz, 1H),4.01 (d, J = 3.0 Hz, 3H), 2.81-2.73 (m, 1H), 1.71 (s, 3H), 0.81-0.78 (m,3H) ppm. 1185-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-3-carboxamide ESI-MS m/z calc. 473.1374,found 474.46 (M+1)⁺; Retention time: 2.24 minutes ¹H NMR (400 MHz,Chloroform-d) δ 8.88 (d, J = 2.3 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.60(s, 1H), 8.49 (t, J = 2.2 Hz, 1H), 7.10-7.06 (m, 1H), 6.90 (td, J = 9.2,7.5 Hz, 1H), 6.32 (br. s, 1H), 5.88 (br. s, 1H), 5.04 (d, J = 11.0 Hz,1H), 4.11 (dd, J = 11.1, 8.1 Hz, 1H), 4.01 (d, J = 3.0 Hz, 3H),2.80-2.70 (m, 1H), 1.69 (s, 3H), 0.80-0.74 (m, 3H) ppm. 1194-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methylpyridine-2-carboxamide ESI-MS m/z calc.487.153, found 488.13 (M+1)⁺; Retention time: 2.54 minutes ¹H NMR (400MHz, Chloroform-d) δ 8.89 (s, 1H), 8.58 (s, 1H), 8.32 (s, 1H), 7.71 (s,1H), 7.12-7.08 (m, 1H), 6.90 (td, J = 9.2, 7.5 Hz, 1H), 5.54 (s, 1H),5.05 (d, J = 11.0 Hz, 1H), 4.08 (dd, J = 11.0, 7.8 Hz, 1H), 4.00 (d, J =3.0 Hz, 3H), 2.80-2.72 (m, 1H), 2.32 (s, 3H), 1.68 (d, J = 0.7 Hz, 3H),0.78 (td, J = 4.9, 2.4 Hz, 3H) ppm. 1202-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-4-carboxamide ESI-MS m/z calc. 473.1374,found 474.1 (M+1)⁺; Retention time: 2.37 minutes ¹H NMR (400 MHz,Chloroform-d) δ 9.05 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 8.42 (s, 1H),7.55 (dd, J = 5.0, 1.6 Hz, 1H), 7.12-7.08 (m, 1H), 6.94-6.87 (m, 1H),6.24 (s, 1H), 5.68 (s, 1H), 5.03 (d, J = 11.2 Hz, 1H), 4.10 (dd, J =11.0, 8.2 Hz, 1H), 3.99 (d, J = 3.0 Hz, 3H), 2.78-2.70 (m, 1H), 1.69 (s,3H), 0.80-0.77 (m, 3H) ppm. 1216-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyrimidine-4-carboxamide ESI-MS m/z calc. 474.1326,found 475.17 (M+1)⁺; Retention time: 2.3 minutes ¹HNMR (400 MHz,Chloroform-d) δ 9.22 (br s, 1H), 8.67 (d, J = 5.5 Hz, 1H), 8.27 (d, J =5.5 Hz, 1H), 7.81 (br s, 1H), 7.07-7.03 (m, 1H), 6.90 (dd, J = 16.9, 8.7Hz, 1H), 5.85 (br s, 1H), 5.02 (d, J = 11.0 Hz, 1H), 4.07 (dd, J = 11.0,8.7 Hz, 1H), 3.99 (d, J = 1.8 Hz, 3H), 2.77-2.69 (m, 1H), 1.69 (s, 3H),0.78 (d, J = 6.4 Hz, 3H) ppm.

The following compound was made using a method similar to that describedin Example 23, except that ethyl 4-amino-5-fluoropyridine-2 carboxylatewas used as coupling partner in the amide formation step 8 in place ofmethyl 6-aminopyridine-2-carboxylate and in step 9, the product wasfurther purified by MDAP (XBridge C18, 19 × 150 mm, 5 µm) usingacetonitrile and water containing 0.1% ammonium hydroxide (30-80% over10 minutes) before freeze drying:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1224-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-fluoro-pyridine-2-carboxamide ESI-MS m/z calc.491.128, found 492.1 (M+1)⁺; Retention time: 2.57 minutes ¹H NMR (400MHz, Chloroform-d) δ 9.10 (d, J = 6.4 Hz, 1H), 8.85 (s, 1H), 8.37 (d, J= 1.8 Hz, 1H), 7.61 (s, 1H), 7.10-7.06 (m, 1H), 6.94-6.87 (m, 1H), 5.48(s, 1H), 5.05 (d, J = 11.0 Hz, 1H), 4.08 (dd, J = 10.8, 8.0 Hz, 1H),4.00 (d, J = 3.0 Hz, 3H), 2.76 (t, J = 7.8 Hz, 1H), 1.68 (s, 3H),0.80-0.77 (m, 3H) ppm.

The following compound was made using a method similar to that describedin Example 23, except step 9 was omitted and 5-amino-2-fluorobenzamidewas used as a coupling partner in step 8:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 123(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide ESI-MS m/z calc. 490.1327, found 491.43 (M+1)⁺;Retention time: 2.5 minutes ¹H NMR (400 MHz, Chloroform-d) δ 8.55 (s,1H), 8.16 (qd, J = 4.5, 3.0 Hz, 1H), 7.89 (q, J = 3.2 Hz, 1H), 7.12-7.04(m, 2H), 6.88 (td, J = 9.2, 7.6 Hz, 1H), 6.77-6.69 (m, 1H), 5.92 (s,1H), 5.00 (d, J = 11.0 Hz, 1H), 4.07 (dd, J = 10.9, 8.1 Hz, 1H), 3.99(d, J = 2.7 Hz, 3H), 2.77-2.70 (m, 1H), 1.68 (s, 3H), 0.79-0.76 (m, 3H)ppm.

The following compound was made using a method similar to that describedin Example 23, except that methyl5-deuterio-4-aminopyridine-2-carboxylate was used in place of methyl6-aminopyridine-2-carboxylate in Step 8. Purification was performed bynormal phase chromatography (Biotage Isolera, 12 g, SiliaSep 25 µmSilicycle flash cartridge) using heptane-ethyl acetate (0 to 100%).

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1245-deuterio-4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 474.1437,found 475.15 (M+1)⁺; Retention time: 2.51 minutes ¹H NMR (400 MHz,Chloroform-d) δ 8.73 (br s, 1H), 8.45 (s, 1H), 7.95 (s, 1H), 7.88 (br s,1H), 7.10-7.06 (m, 1H), 6.93-6.87 (m, 1H), 5.63 (br s, 1H), 5.02 (d, J =11.0 Hz, 1H), 4.08 (dd, J = 11.0, 8.2 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H),2.79-2.71 (m, 1H), 1.68 (s, 3H), 0.80-0.77 (m, 3H) ppm.

Example 244-[[(2R,35,45,5R)-3-(3,4-Difluoro-2-Methoxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]-3-Fluoro-Pyridine-2-Carboxamide(126)

Step 1

To an ice cooled solution of(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (99 mg, 0.2571 mmol) (see Example 23, step 7) in2-methyltetrahydrofuran (1 mL) was added DMF (1.8880 mg, 2 µL, 0.0258mmol) followed by careful addition of oxalyl chloride (58.200 mg, 40 µL,0.4585 mmol). The reaction mixture warmed to room temperature andstirred for 1 hr. The reaction mixture was concentrated in vacuo and theresidue dissolved in 2-methyltetrahydrofuran (0.4 mL). To this, wasadded ammonium hydroxide (28% w/w) (360.00 mg, 0.4 mL of 28 %w/v, 10.272mmol). The resulting mixture was stirred at room temperature for 1.5 hr.The reaction mixture was quenched with water (10 mL) and partitionedwith ethyl acetate (15 mL). The layers were separated and the organicphase was washed with brine (10 mL), dried (sodium sulfate), filteredand concentrated under reduced pressure to give(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(105 mg, 98%) as a pale yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.51 (s,1H), 7.35-7.31 (m, 1H), 7.16-7.12 (m, 2H), 4.82 (d, J = 10.8 Hz, 1H),4.06-4.00 (m, 1H), 3.93 (d, J = 2.3 Hz, 3H), 2.69-2.62 (m, 1H), 1.55 (s,3H), 0.67 (dd, J = 7.3, 2.1 Hz, 3H) ppm.

Step 2

(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(100 mg, 0.2354 mmol), methyl 4-chloro-3-fluoro-pyridine-2-carboxylate(144 mg, 0.2583 mmol), Pd(OAc)₂ (11 mg, 0.0490 mmol), cesium carbonate(153 mg, 0.4696 mmol) and Xantphos (55 mg, 0.0951 mmol) were suspendedin 2-MeTHF (2 mL) and heated to 100° C. for 16 hrs. The reaction wasdiluted with ethyl acetate (5 mL) and washed with water (5 mL), followedby brine (5 mL). The organic layer was dried (sodium sulfate), filteredand concentrated in vacuo. Purification by flash chromatography (BiotageIsolera, 12 g SiliaSep 25 µm Silicycle flash cartridge, loaded from DCM,0 to 100% ethyl acetate in heptane) to give methyl4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxylate(42 mg, 29%) as a pale yellow oil. ESI-MS m/z calc. 506.1276, found507.5 (M+1)⁺.

Step 3

A mixture of methyl4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxylate(37 mg, 0.0599 mmol) and ammonia (7 M in methanol) (1 mL of 7 M, 7.0000mmol) in methanol (0.5 mL) was stirred for 1 h and then concentrated invacuo. Purification by MDAP (XBridge C18, 19 × 150 mm, 5 µm) usingacetonitrile and water containing 0.1% ammonium hydroxide (30-80% over10 minutes) to give4-[[(2R,3S.4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-fluoro-pyridine-2-carboxamide(126, 5.9 mg, 20%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ9.09 (br s, 1H), 8.46 (t, J = 5.3 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H),7.69 (br s, 1H), 7.11-7.07 (m, 1H), 6.94-6.87 (m, 1H), 5.53 (br s, 1H),5.04 (d, J = 11.0 Hz, 1H), 4.06 (dd, J = 11.3, 7.7 Hz, 1H), 4.00 (d, J =2.7 Hz, 3H), 2.79-2.71 (m, 1H), 1.68 (s, 3H), 0.80-0.78 (m, 3H) ppm.ESI-MS m/z calc. 491.128, found 492.13 (M+1)⁺.

The following compounds were made using a method similar to thatdescribed in Example 24, except that different coupling partners wereused in the amide coupling step 2 and, for compounds 128 and 127, thepurification in step 3 was conducted by reverse phase chromatography(Biotage Isolera, 12 g, SiliaSepC18 Monomeric 25 µm Silicycle flashcartridge) using a gradient of acetonitrile containing 0.1% ammoniumhydroxide and water containing 0.1% ammonium hydroxide before freezedrying:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 1284-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-methylpyridine-2-carboxamide ESI-MS m/z calc.487.153, found 488.12 (M+1)⁺; Retention time: 2.58 minutes ¹H NMR (400MHz, Chloroform-d) δ 8.75 (s, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.90 (d, J= 2.7 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.11-7.07 (m, 1H), 6.90 (td, J= 9.2, 7.5 Hz, 1H), 5.68 (d, J = 3.9 Hz, 1H), 5.02 (d, J = 11.0 Hz, 1H),4.08 (dd, J = 11.2, 8.0 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 2.79-2.71 (m,1H), 2.50 (d, J = 4.4 Hz, 3H), 1.69 (s, 3H), 0.80-0.78 (m, 3H) ppm. 1274-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-6-fluoro-pyridine-2-carboxamide ESI-MS m/z calc.491.128, found 492.41 (M+1)⁺; Retention time: 2.66 minutes ¹H NMR (400MHz, Chloroform-d) δ 8.77 (br s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.76 (s,1H), 7.51 (br s, 1H), 7.08-7.04 (m, 1H), 6.94-6.87 (m, 1H), 5.56 (br s,1H), 5.02 (d, J = 11.0 Hz, 1H), 4.06 (dd, J = 11.2, 8.0 Hz, 1H), 4.00(d, J = 2.7 Hz, 3H), 2.79-2.71 (m, 1H), 1.68 (s, 3H), 0.80-0.77 (m, 3H)ppm. 1284-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-3-methylpyridine-2-carboxamide ESI-MS m/z calc.487.153, found 488.17 (M+1)⁺; Retention time: 2.42 minutes ¹H NMR (400MHz, Chloroform-d) δ 8.88 (br s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.32 (d,J = 5.5 Hz, 1H), 7.93 (br s, 1H), 7.12-7.08 (m, 1H), 6.91 (dd, J = 16.7,8.9 Hz, 1H), 5.54 (br s, 1H), 5.06 (d, J = 11.0 Hz, 1H), 4.08 (dd, J =11.0, 7.8 Hz, 1H), 4.00 (d, J = 2.7 Hz, 3H), 2.80-2.75 (m, 1H), 2.71 (s,3H), 1.69 (s, 3H), 0.80 (dd, J = 7.3, 1.8 Hz, 3H) ppm. 1293-deuterio-4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy- ESI-MS m/z calc.474.1437, found 475.21 ¹H NMR (400 MHz, Chloroform-d) δ 8.77 (s,phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide (M+1)⁺; Retention time: 2.48minutes 1H), 8.44 (dd, J = 10.8, 4.8 Hz, 1H), 8.18-8.12 (m, 1H), 7.86(s, 1H), 7.10-7.06 (m, 1H), 6.90 (td, J = 9.2, 7.3 Hz, 1H), 5.66 (s,1H), 5.02 (d, J = 11.0 Hz, 1H), 4.08 (dd, J = 11.0, 8.2 Hz, 1H), 3.99(d, J = 2.7 Hz, 3H), 2.79-2.70 (m, 1H), 1.68 (s, 3H), 0.80-0.77 (m, 3H)ppm. 1306-deuterio-4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide ESI-MS m/z calc. 474.1437,found 475.19 (M+1)⁺; Retention time: 2.5 minutes ¹H NMR (400 MHz,Chloroform-d) δ 8.67 (br s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 7.93 (d, J =2.3 Hz, 1H), 7.84 (br s, 1H), 7.10-7.06 (m, 1H), 6.90 (td, J = 9.2, 7.3Hz, 1H), 5.59 (br s, 1H), 5.01 (d, J = 11.0 Hz, 1H), 4.07 (dd, J = 11.2,8.0 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H), 2.78-2.71 (m, 1H), 1.68 (s, 3H),0.80-0.77 (m, 3H) ppm.

Example 25Rel-(2s,3r,4r,5s)-4-[[3-(3,4-Difluoro-2-Methyl-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(131), Rel-(2r, 3s,4s,5r)-4-[[3-(3,4-Difluoro-2-MethylPhenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]pyridine-2-Carboxamide(132), Rel-(2r, 3s, 4r,5s)-4-[[3-(3,4-Difluoro-2-Methyl-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(133) andRel-(2s,3r,4s,5r)-4-[[3-(3,4-Difluoro-2-Methyl-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(134)

Step 1

To a 3 neck 1 litre flask hooked up with a thermometer and air condenseris added ethylrac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate(42 g, 108.7 mmol) and 1,4-dioxane (500 mL). The mixture was stirred anddegassed and flushed with nitrogen. KOAc (32 g, 326.1 mmol) was addedfollowed by bis(pinacolato)diboron (32 g, 126.0 mmol). The reactionmixture was evacuated and back filled with nitrogen (×3). Pd(dppf)Cl₂ (4g, 5.467 mmol) was added to this reaction mixture which was heated to60° C. first then when stable, the temperature was increased to 80° C.(to avoid exotherm). The reaction was allowed to proceed with stirringat 80° C. under nitrogen for 20 hours. The reaction mixture was thencooled to ambient temperature and diluted with ethyl acetate (300 mL)and water (100 mL). The mixture was filtered through a pad of celite,washing several times with ethyl acetate until no more product came off(5 × 100 ml). The filtrate is then separated, and the aqueous layer wasextracted with ethyl acetate twice (100 mL). The combined organic layerswere dried and filtered using Whatman 1PS hydrophobic phase separatorfilter paper. The filtrates were concentrated in vacuo to give 47 g of abrown oil. The crude product (47 g) was absorbed onto diatomaceous earth(Telos nm) and passed through a Florisil (magnesium silicate) pad,washing with 100% heptane until no more product came off (4 fractions intotal). The filtrates were combined and concentrated in vacuo to giveethylrac-(4S,5R)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(47 g, 95%) as a thick viscous yellow oil. ¹H NMR (500 MHz,Chloroform-d) δ 4.33 - 4.23 (m, 2H), 3.27 - 3.18 (m, 1H), 1.55 (d, J =1.1 Hz, 3H), 1.32 (s, 12H), 1.28 (d, J = 2.3 Hz, 2H), 1.24 (s, 3H) ppm.ESI-MS m/z calc. 364.1669, found 365.3 (M+1)⁺.

Step 2

To a solution ofrac-(4S,5R)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(3 g, 7.414 mmol), 1-bromo-3,4-difluoro-2-methyl-benzene (1.4 g, 6.763mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (350 mg, 0.4286 mmol) in 1,4-dioxane (60mL), was added an aqueous solution of K₃PO₄ (8 mL of 2 M, 16.00 mmol).The mixture was degassed and placed under a nitrogen atmosphere. Thereaction was stirred at 100° C. for 2 hours. The mixture was partitionedbetween water and ethyl acetate. The aqueous layer was extracted 3 timeswith ethyl acetate. The organics were combined, dried and filtered usingWhatman 1PS hydrophobic phase separator filter paper. The filtrates wereconcentrated in vacuo to give a brown oil. Purification by flashchromatography (RF combiflash companion, 24 g pre-packed gold silicacolumn, 0 to 100% EtOAc in heptane gave ethylrac-(4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(2.21 g, 67%) as a pale yellow oil. ¹H NMR (500 MHz, Methanol-d₄) δ 7.10(dt, J = 10.3, 8.4 Hz, 1H), 6.90 (s, 1H), 4.14 - 4.00 (m, 2H), 3.54 (d,J = 8.2 Hz, 1H), 2.19 (d, J = 2.7 Hz, 3H), 1.70 (d, J = 1.2 Hz, 3H),1.09 (dq, J = 7.5, 2.4 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H) ppm. ESI-MS m/zcalc. 364.10977, found 365.2 (M+1)⁺.

Step 3

A pressure tube was loaded with magnesium powder (200 mg, 8.229 mmol)and purged with nitrogen. To the reaction vessel was added a solution ofethylrac-(4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(2.02 g, 5.545 mmol) in MeOH (30 mL). The mixture was degassed andplaced under a nitrogen atmosphere. A few drops of 1,2-dibromoethane (5µL, 0.05802 mmol) were added. The reaction mixture was stirredvigorously and heated at 70° C. for 6 hrs.

A further 3 consecutive portions of magnesium powder (200 mg, 8.229mmol) were added followed by a drop of 1,2-dibromoethane (5 µL, 0.05802mmol). The mixture was stirred overnight at 70° C. for 88 hours. Thereaction mixture was cooled to 0° C. prior to opening the pressurevessel. The cooled mixture is added dropwise to a cooled beakercontaining 1 M HCl. The reaction was stirred at 0° C. for 30 minutesuntil all Mg solids dissolved. The mixture was concentrated in vacuo toremove the MeOH. The remaining aqueous solution was extracted with ethylacetate (x3). The combined organic extracts were dried and filteredusing a Whatman 1PS hydrophobic phase separator filter paper. Thefiltrates were concentrated in vacuo to give methylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.487 g, 76%) as the major diastereomer as a colourless oil. ESI-MS m/zcalc. 352.10977, found 353.0 (M+1)⁺.

Step 4

To a cooled solution of methylrac-(2S,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.487 g, 4.221 mmol) in 2-Me-THF (20 mL) was added potassiumtert-butoxide (1.4 g, 12.48 mmol) (internal temperature increased to ~5°C.) and the reaction was stirred for 1 hour at ambient temperature. Thereaction mixture colour turned yellow on addition of potassiumt-butoxide. The reaction was diluted with ethyl acetate and 1 N NaOH.The aqueous layer was separated. The organics were washed further with 1M NaOH (×2). The combined organic layers were dried and filtered using aWhatman 1PS hydrophobic phase separator filter paper. The filtrates wereconcentrated in vacuo to giverac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (1.01 g, 71%) as the major diastereomer as a colourless oil. ESI-MSm/z calc. 338.09415, found 337.0 (M-1)⁻.

Step 5

To a solution ofrac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (200 mg, 0.591 mmol) and DMF (2 µL, 0.026 mmol) in2-methyl-tetrahydrofuran (4.8 mL) stirring at 0° C. under nitrogen wasadded oxalyl chloride (154.2 mg, 106.0 µL, 1.215 mmol). The mixture waswarmed up to room temperature over 30 minutes. The reaction mixture wasconcentrated in vacuo and the residue dissolved in2-methyl-tetrahydrofuran (4.8 mL). This solution was added to an icecooled solution of methyl 4-aminopyridine-2-carboxylate (110.7 mg, 0.728mmol) and TEA (278.6 mg, 383.7 µL, 2.753 mmol) in2-methyl-tetrahydrofuran (4.8 mL). The resulting mixture was stirred andwarmed to ambient temperature over 18 hrs. The reaction mixture wasquenched with water (5 mL) and the layers separated. The aqueous layerwas extracted with EtOAc (2 × 10 mL). The combined organics extractswere dried and filtered using a Whatman 1PS hydrophobic phase separatorfilter paper. The filtrates werer concentrated in vacuo to give an oil.Purification by flash chromatography (RF combiflash companion, 4 gpre-packed silica column, 0-50% EtOAc:EtOH (3:1) containing 2% NH₄OH inheptane) gave methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(235 mg, 59%) as the major diastereomer. ESI-MS m/z calc. 472.14215,found 473.3 (M+1)⁺; 471.3 (M-1)⁻.

Step 6

Methylrac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(235 mg, 0.4975 mmol) was taken up in a solution of ammonia (1 mL of 7M, 7.000 mmol) in methanol (10 mL) and stirred at room temperature for 2hours. The reaction mixture was concentrated in vacuo to giverac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(221.4 mg, 49%) as the major diastereomer as a yellow oil. ESI-MS m/zcalc. 457.1425, found 458.4 (M+1)⁺; 456.4 (M-1)⁻.

Step 7

rac-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(221.4 mg, 49%) was purified by chiral SFC using a Chiralpak IG column,5um particle size, 25 cm × 10 mm from Daicel on a Minigram SFCinstrument from Berger Instruments followed by reversed phase HPLC-MSusing a Xbridge C18 OBD column (150 × 19 mm, 5 mm particle size) fromWaters (using gradient elution over 16.0 minutes; mobile phase A = H₂O(0.1% ammonium hydroxide), mobile phase B = CH₃CN. Flow rate = 19mL/min; injection volume = <2000 µL, column temperature = 25° C.) togive:

First Eluting Isomer (rt = 3.93 min):rel-(2S,3R,4R,5S)-4-[[3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(131, 4.1 mg, 14%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.47 (d,J = 5.5 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H),7.59 (s, 1H), 7.26 (q, J = 9.0 Hz, 1H), 7.18 (dd, J = 9.0, 4.3 Hz, 1H),5.16 (d, J = 10.4 Hz, 1H), 4.19 (dd, J = 10.5, 7.5 Hz, 1H), 2.85 (p, J =7.5 Hz, 1H), 2.28 (d, J = 2.1 Hz, 3H), 1.64 (s, 3H), 0.71 - 0.66 (m, 3H)ppm. ESI-MS m/z calc. 457.1425, found 458.2 (M+1)⁺; 456.2 (M-1)⁻.

Second Eluting Isomer (rt = 4.33 min):rel-(2R,3S,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(132, 3.6 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.69 (s, 1H), 8.48 (d,J = 5.5 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.04 (s, 1H), 7.82 (dd, J =5.5, 2.2 Hz, 1H), 7.59 (s, 1H), 7.26 (q, J = 9.0 Hz, 1H), 7.17 (dd, J =8.9, 4.3 Hz, 1H), 5.16 (d, J = 10.5 Hz, 1H), 4.19 (dd, J = 10.4, 7.6 Hz,1H), 2.85 (p, J = 7.5 Hz, 1H), 2.27 (d, J = 2.2 Hz, 3H), 1.63 (s, 3H),0.73 - 0.62 (m, 3H) ppm. ESI-MS m/z calc. 457.1425, found 458.2 (M+1)⁺;456.2 (M-1)⁻.

Third Eluting Isomer (rt = 5.05 min):rel-(2R,3S,4R,5S)-4-[[3-(3,4-difluoro-2-methylphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(133, 2.4 mg, 8%). ESI-MS m/z calc. 457.1425, found 458.2 (M+1)⁺; 456.2(M-1)⁻.

Fourth Eluting Isomer (rt = 6.87 min):rel-(2S,3R,4S,5R)-4-[[3-(3,4-difluoro-2-methyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(134, 2.2 mg, 8%). ESI-MS m/z calc. 457.1425, found 458.2 (M+1)⁺; 456.2(M-1)⁻.

The following compounds were made using the method described in Example25, except that the conditions used for the Suzuki coupling step 2 weresimilar to the ones used in Example 11 step 3 starting with1-bromo-4-(difluoromethyl)-3-fluoro-2-methoxy-benzene. The reductionstep 3 was conducted with Pd(OH)₂ using an atmospheric pressure ofhydrogen in conditions similar to those described in Example 11 step 4.In step 7, purification was performed by chiral SFC using a ChiralartAmylose-SA column, 5 µm particle size, 25 cm x 20 mm from YMC Co., Ltdon a Minigram SFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 135rel-(2S,3R,4R,5S)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide ESI-MS m/zcalc. 505.14362, found 506.3 (M+1)⁺; 504.3 (M-1)⁻; Retention time: 3.28minutes (first eluting isomer by SFC on Chiralart Amylose-SA column, rt= 3.36 min) 136rel-(2R,3S,4S,5R)-4-[[3-[4-(difluoromethyl)-3-fluoro-2-methoxy-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl] amino]pyridine-2-carboxamide ESI-MS m/zcalc. 505.14362, found 506.3 (M+1)⁺; 504.3 (M-1)⁻; Retention time: 3.28minutes (second eluting isomer by SFC on Chiralart Amylose-SA column, rt= 4.40 min)

Example 26Rel-(2S,3R,4R,5S)-4-[[3-[2-Methoxy-6-(Trifluoromethyl)-3-Pyridyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(137) andRel-(2R,3S,4S,5R)-4-[[3-[2-Methoxy-6-(Trifluoromethyl)-3-Pyridyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(138)

Step 1

A mixture of ethylrac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate(3.48 g, 9.00 mmol), [2-methoxy-6-(trifluoromethyl)-3-pyridyl]boronicacid (1.977 g, 8.95 mmol), Na₂CO₃ (1.9 g, 17.93 mmol) and Pd(PPh₃)₄ (520mg, 0.45 mmol) in PhMe (50 mL), MeOH (5 mL) and water (5 mL) wasdegassed before being heated at 80° C. for 16 hours. The mixture wascooled to ambient temperature and diluted with EtOAc. The organic layerwas washed with brine, dried (MgSO₄), filtered and concentrated invacuo. Purification by flash chromatography (40 g SiO₂, 0 to 30% EtOAcin petrol) gave ethylrac-(4S,5R)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(2.67 g, 72%) as a colourless oil. ESI-MS m/z calc. 413.10617, found414.6 (M+1)⁺.

Step 2

EtOH (50 mL) was added torac-(4S,5R)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(2.16 g, 5.226 mmol) and Pd/C (wet, Degussa, 5.2 g, 4.89 mmol). Themixture was degassed and stirred under a balloon of hydrogen for 16hours before being filtered through celite, washing with methanol. Thefiltrate was concentrated in vacuo. Pd/C (wet, Degussa, 5.2 g, 4.89mmol) was added to the residue and the mixture resuspended in EtOH (50mL). The mixture was degassed and stirred under a balloon of hydrogenfor 16 hours before being filtered through celite, washing withmethanol. The filtrate was concentrated in vacuo to give a mixture ofdiastereomers including ethylrac-(2S,3S,4S,5R)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(2.01 g, 93%) as an off-white solid. ESI-MS m/z calc. 415.12183, found416.7 (M+1)⁺.

Step 3

To a solution of ethylrac-(2S,3S,4S,5R)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylateobtained from Step 2 (2.01 g, 4.84 mmol) in THF (32 mL) was addedpotassium tert-butoxide (1.63 g, 14.53 mmol). The reaction was stirredfor 3 days, then diluted with EtOAc and quenched with 1 M HCl. Theaqueous layer was extracted with EtOAc, and the combined organic layersdried (MgSO₄), filtered and concentrated in vacuo to give a mixture ofdiastereomers includingrac-(2R,3S,4S,5R)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (2.09 g), which was used without further purification.

Step 4

To a solution ofrac-(2R,3S,4S,5R)-3-(2-methoxy-6-(trifluoromethyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid obtained from Step 3 (500 mg, 1.29 mmol) in DCM (11 mL) stirring at0° C. was added DMF (10 µL, 0.13 mmol) and oxalyl chloride (340 µL, 3.90mmol). The reaction mixture was concentrated in vacuo and the residuedisolved in DCM (8 mL) and added dropwise to a solution of methyl4-aminopyridine-2-carboxylate (300 mg, 1.97 mmol) and Et₃N (1000 µL,7.18 mmol) in DCM (4 mL) stirring at 0° C. DMAP (15 mg, 0.1228 mmol) wasadded and the reaction stirred at this temperature for 10 mins beforebeing warmed to ambient temperature. After stirring overnight thereaction mixture was diluted in DCM and washed with 1 M HC1 solution.The organic layer was dried (MgSO₄), filtered and concentrated in vacuo,directly onto silica gel. Purification by flash chromatography (40 gSiO₂, 0 to 100% EtOAc in petrol) gave a mixture of diastereomersincluding methylrac-(2R,3S,4S,SR)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(252 mg, 37%). ESI-MS m/z calc. 521.13855, found 522.6 (M+1)⁺; 520.7(M-1)⁻.

Step 5

Methylrac-(2R,3S5.4S8,5R)-4-[[3-|2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylateobtained from Step 4 (252 mg, 0.4833 mmol) was dissolved in methanolicammonia (15 mL of 7 M, 105.0 mmol) and stirred for 16 hours. Thereaction mixture was concentrated in vacuo to give a mixture ofdiastereomers includingrac-(2R,3S,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(250 mg).

Step 6

rac-(2R,3S,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideobtained from Step 5 (250 mg, 0.4937 mmol) was separated by chiral SFCusing a (R,R)-Whelk-O1 column, 5 µm particle size, 25 cm × 21.2 mm fromRegis Technologies to give:

First Eluting Isomers (rt = 1.04 min and 1.10 min): a mixture of twostereoisomers of4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,which were not purified further.

Second Eluting Isomers (rt = 1.28 min and 1.34 min): a mixture of twostereoisomers of4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide.Further separation steps are listed below.

Third Eluting Isomer (rt = 1.52 min): a stereoisomer of4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,that was not characterized further.

Fourth Eluting Isomer (rt = 1.93 min): rel-(2R,3S,4S,5R)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(138, 26.4 mg, 10%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.64 (s, 1H), 8.49 (d,J = 5.5 Hz, 1H), 8.30 (dd, J = 2.2, 0.6 Hz, 1H), 8.05 (d, J = 2.8 Hz,1H), 7.98 (d, J = 7.7 Hz, 1H), 7.85 (dd, J = 5.5, 2.2 Hz, 1H), 7.60 (d,J = 2.9 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 5.25 (d, J = 9.5 Hz, 1H),4.22 (t, 1H), 3.96 (s, 3H), 2.93 (p, J = 7.5 Hz, 1H), 1.63 (s, 3H),0.76 - 0.66 (m, 3H) ppm. ESI-MS m/z calc. 506.1389, found 507.6 (M+1)⁺;505.7 (M-1)⁻.

The second eluting peak was further separated by chiral SFC using aChiralpak AS-H column, 5 µm particle size, 25 cm x 10 mm from Daicel ona Minigram SFC instrument from Berger Instruments to give:

First Eluting Isomer (rt = 3.01 min): rel-(2S,3R,4R,5S)-4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(137, 18.4 mg, 7%). ESI-MS m/z calc. 506.1389, found 507.5 (M+1)⁺; 505.5(M-1)⁻.

Second Eluting Isomer (rt = 4.09 min): a stereoisomer of4-[[3-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide,that was not characterized further.

The following compound was made using the method described above, exceptthat the conditions used for the Suzuki coupling step 1 were similar tothe ones used in Example 13 step 4 starting with4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine.The reduction step 2 was conducted using 5 atm of hydrogen. The chiralSFC separation step 6 was not carried out and the product was isolatedas a pair of enantiomers:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 139rac-(2R,3S,4S,5R)-4-[[3-[4-methoxy-6-(trifluoromethyl)-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 506.1389, found 507.1 (M+1)⁺; Retention time: 2.327minutes ¹H NMR (301 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.64 (s, 1H),8.46 (d, J = 5.5 Hz, 1H), 8.16 (dd, J = 5.5, 2.1 Hz, 1H), 7.93 (d, J =2.1 Hz, 1H), 7.84 (br s, 1H), 7.18 (s, 1H), 5.63 (br s, 1H), 5.24 (d, J= 10.7 Hz, 1H), 4.13 (dd, J = 10.8, 8.1 Hz, 1H), 3.97 (d, J = 5.2 Hz,3H), 2.85 (t, J = 7.6 Hz, 1H), 1.70 (s, 3H), 0.80 (d, J = 5.5 Hz, 3H)ppm.

Example 27Rel-(2r,3s,4s,5r)-4-[[3-[6-(Difluoromethyl)-2-Methoxy-3-Pyridyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(140) andRel-(2s,3r,4r,5s)-4-[[3-[6-(Difluoromethyl)-2-Methoxy-3-Pyridyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]pyridine-2-Carboxamide(141)

Step 1: To a 3 neck 1 litre flask hooked up with a thermometer and aircondenser is added ethylrac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate(42 g, 108.7 mmol) and 1,4-dioxane (500 mL). The mixture was stirred anddegassed and flushed with nitrogen. KOAc (32 g, 326.1 mmol) was addedfollowed by bis(pinacolato)diboron (32 g, 126.0 mmol). The reactionmixture was evacuated and back filled with nitrogen (x3). Pd(dppf)Cl₂ (4g, 5.467 mmol) was added to this reaction mixture which was heated to60° C. first then when stable, the temperature was increased to 80° C.(to avoid exotherm). The reaction was allowed to proceed with stirringat 80° C. under nitrogen for 20 hours. The reaction mixture was thencooled to ambient temperature and diluted with ethyl acetate (300 mL)and water (100 mL). The mixture was filtered through a pad of celite,washing several times with ethyl acetate until no more product came off(5 × 100 ml). The filtrate is then separated, and the aqueous layer wasextracted with ethyl acetate twice (100 mL). The combined organic layerswere dried and filtered using Whatman 1PS hydrophobic phase separatorfilter paper. The filtrates were concentrated in vacuo to give 47 g of abrown oil. The crude product (47 g) was absorbed onto diatomaceous earth(Telos nm) and passed through a Florisil (magnesium silicate) pad,washing with 100% heptane until no more product came off (4 fractions intotal). The filtrates were combined and concentrated in vacuo to giveethylrac-(4S,5R)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(47 g, 95%) as a thick viscous yellow oil. ¹H NMR (500 MHz,Chloroform-d) δ 4.33 - 4.23 (m, 2H), 3.27 - 3.18 (m, 1H), 1.55 (d, J =1.1 Hz, 3H), 1.32 (s, 12H), 1.28 (d, J = 2.3 Hz, 2H), 1.24 (s, 3H) ppm.ESI-MS m/z calc. 364.1669, found 365.3 (M+1)⁺.

Step 2

ethylrac-(4S,5R)-4,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(47 g) was dissolved in a 1:2 mixture of water (50 mL) and THF (100 mL).Sodium periodate (50 g, 233.8 mmol) was added and the reaction wasstirred for 1 hour at ambient temperature. The reaction mixture wascooled with an ice bath. 1 M HC1 (60 mL) was added and reaction mixturewas stirred for 60 mins (a white solid precipitates). The mixture wasdiluted with water (50 mL) and ethyl acetate (100 mL). A white solid wasfiltered and washed with ethyl acetate. The filtrate was washed withsodium thiosulphate (shaken vigorously at every wash to remove traces ofiodine) (3 × 50 ml) followed by a brine solution. The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum (keeping water bath at room temp). A creamsolid (23 g) was obtained and triturated with cold heptane to affordrac-((4S,5R)-2-(ethoxycarbonyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)boronicacid (16.66 g, 54%) as a white solid. ¹H NMR (500 MHz, Chloroform-d) δ6.84 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.18 (q, J = 7.3 Hz, 1H), 1.51(d, J = 1.2 Hz, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.32 (dq, J = 7.2, 2.4Hz, 3H) ppm. ESI-MS m/z calc. 282.08865, found 281.2 (M-1)⁻.

Step 3

To a solution ofrac-((4S,SR)-2-(ethoxycarbonyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)boronicacid (902 mg, 3.79 mmol) and Pd(PPh₃)₄ (82 mg, 0.071 mmol) in dioxane(20 mL) was added an aqueous solution of K₂CO₃ (3.5 mL of 2 M, 7.000mmol). The reaction was initially stirred at 100° C. for 2 hours, thenat 115° C. for 3 hours. A further 30 mg of Pd(PPh₃)₄ was added and themixture was stirred for a further 30 mins at reflux. The mixture waspartitioned between water and ethyl acetate. The aqueous layer waswashed twice more with ethyl acetate. The combined organic phases werewashed with brine, dried (MgSO₄) and concentrated in vacuo. Purificationby flash chromatography (SiO₂, 0 to 25% EtOAc in heptane) gave ethylrac-(4S,5R)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(1.05 g, 75%) as a colourless oil. ¹H NMR (500 MHz, Chloroform-d) δ 7.61(d, J = 7.5 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 6.52 (t, J = 55.6 Hz,1H), 4.23 - 4.07 (m, 2H), 3.96 (s, 3H), 3.63 (q, J = 7.4 Hz, 1H), 1.70(d, J = 1.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H), 1.06 (dq, J = 7.3, 2.2Hz, 3H) ppm. ESI-MS m/z calc. 395.1156, found 396.3 (M+1)⁺.

Step 4

A solution of ethylrac-(4S,SR)-3-(6-(difluoromethyl)-2-methoxypyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate(250 mg, 0.632 mmol) in MeOH (50 mL) was added to Pd(OH)₂ (475 mg of 20%w/w, 0.67 mmol) under nitrogen in a Parr flask. The flask was connectedto the Parr shaker and put under an atmosphere of hydrogen (60 psi, 4bar). The reaction was shaken at ambient temperature overnight. Thereaction mixture was carefully filtered through a pad of celite. Thecollected filtrates were concentrated in vacuo to give a ~1:1 mixture ofdiastereomers of ethylrac-(4S,SR)-3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(170 mg, 68%). ESI-MS m/z calc. 397.13126, found 398.2 (M+1)⁺.

Step 5

To a solution of ethylrac-(4S,5R)-3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(160 mg, 0.4027 mmol) in 2-MeTHF (6 mL) was added KOt-Bu (95 mg, 0.8466mmol) and the reaction was stirred at ambient temperature for 30minutes. The reaction was quenched by addition of a 2 M HC1 solution.Ethyl acetate was added. The separated organic layer was washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo to giverac-(4S,5R)-3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (150 mg, 100%) as a colourless oil, one of the diastereoisomersbeing the major component. ESI-MS m/z calc. 369.09995, found 368.1(M-1)⁻.

Step 6

To a solution ofrac-(4S,5R)-3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (150 mg, 0.4062 mmol) and methyl 4-aminopyridine-2-carboxylate (79mg, 0.5192 mmol) in ethyl acetate (3 mL) was added TEA (170 µL, 1.220mmol) and T3P (325 µL of 50 %w/w, 0.5460 mmol). The reaction was stirredat 50° C. for 3 hours. The reaction mixture was diluted with water andethyl acetate. The aqueous layer was further extracted with ethylacetate. The combined organics were washed with brine, dried (MgSO₄),filtered and concentrated in vacuo. Purification by flash chromatography(SiO₂, 75% EtOAc in heptane) gave the main diastereoisomer methylrac-(2R,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(70 mg, 34%) as a colourless oil. ¹H NMR (500 MHz, Chloroform-d) δ 8.63(d, J = 5.5 Hz, 1H), 8.58 (d, J = 10.2 Hz, 1H), 8.08 (d, J = 2.1 Hz,1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 6.52 (t,J = 55.6 Hz, 1H), 5.10 (d, J = 11.1 Hz, 1H), 4.05 (dd, J = 11.1, 7.8 Hz,1H), 4.00 (s, 3H), 3.98 (s, 3H), 2.92 (q, J = 7.6 Hz, 1H), 1.72 (d, J =2.9 Hz, 3H), 0.77 (dt, J = 7.5, 2.3 Hz, 3H) ppm. ESI-MS m/z calc.503.14795, found 504.4 (M+1)⁺; 502.3 (M-1)⁻.

Step 7

rac-(2R,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(70 mg, 0.1390 mmol) was dissolved in methanolic ammonia (3 mL of 7 M,21.00 mmol) and stirred at ambient temperature overnight. The reactionmixture was concentrated in vacuo to giverac-(2R,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(26 mg, 38%). ESI-MS m/z calc. 488.1483, found 489.3 (M+1)⁺; 487.3(M-1)⁻.

Step 8

rac-(2R,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(26 mg, 0.053 mmol) was separated by chiral SFC using a Luxi-Cellulose-5 column, 5 µm particle size, 25 cm x 10 mm from Phenomenex,Inc. on a Minigram SFC instrument from Berger Instruments to give:

First Eluting Isomer (rt = 4.12 min):rel-(2R,3S,4S,5R)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(140, 8.2 mg). ¹H NMR (500 MHz, Methanol-d₄) δ 8.48 (d, J = 5.6 Hz, 1H),8.27 (d, J = 2.2 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz, 1H), 7.85 (d, J =7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.59 (t, J = 55.5 Hz, 1H), 5.19(d, J = 10.1 Hz, 1H), 4.26 (t, J = 9.0 Hz, 1H), 4.00 (s, 3H), 2.95 (p, J= 7.6 Hz, 1H), 1.67 (s, 3H), 0.79 (dd, J = 7.7, 2.6 Hz, 3H) ppm; amideNH and NH₂ protons not observed. ESI-MS m/z calc. 488.1483, found 489.4(M+1)⁺; 487.3 (M-1)⁻.

Second Eluting Isomer (rt = 4.71 min):rel-(2S,3R,4R,5S)-4-[[3-[6-(difluoromethyl)-2-methoxy-3-pyridyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(141, 10.1 mg). ¹H NMR (500 MHz, Methanol-d₄) δ 8.52 (d, J = 5.7 Hz,1H), 8.38 (d, J = 2.1 Hz, 1H), 7.99 (dd, J = 5.8, 2.2 Hz, 1H), 7.86 (d,J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.59 (t, J = 55.5 Hz, 1H),5.22 (d, J = 10.1 Hz, 1H), 4.33 - 4.23 (m, 1H), 4.00 (s, 3H), 2.96 (p, J= 7.6 Hz, 1H), 1.68 (d, J = 1.4 Hz, 3H), 0.80 (dq, J = 7.4, 2.3 Hz, 3H)ppm; amide NH and NH₂ protons not observed. ESI-MS m/z calc. 488.1483,found 489.3 (M+1)⁺; 487.3 (M-1)⁻.

The following compounds were made using a similar method to thatdescribed in Example 27, except that 2-bromo-3-methoxypyridine was usedin place of 3-bromo-6-(difluoromethyl)-2-methoxy-pyridine in step 3 andthe conditions used for the reduction step 4 were similar to the onesused in Example 1 step 2. In step 8, purification was performed bychiral SFC using a Chiralpak IC column for 142 and 143 and using aChiralcel OD-H column for 144 and 145, 5 µm particle size, 25 cm x 20 mmfrom Daicel on a Minigram SFC instrument from Berger Instruments:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) 142rel-(2S,3R,4R,5S)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 438.1515, found 440.3 (M+1)⁺; 437.2 (M-1)⁻; Retentiontime: 2.84 minutes ¹H NMR (500 MHz, Methanol-d4) δ 8.46 (d, J = 5.5 Hz,1H), 8.22 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 4.8, 1.3 Hz, 1H), 7.88 (dd,J = 5.5, 2.2 Hz, 1H), 7.38 (dd, J = 8.3, 1.4 Hz, 1H), 7.28 (dd, J = 8.3,4.8 Hz, 1H), 5.61 (d, J = 10.4 Hz, 1H), 4.39 (dd, J = 10.4, 7.6 Hz, 1H),3.91 (s, 3H), 3.01 (p, J = 7.5 Hz, 1H), 1.62 (d, J = 1.4 Hz, 3H), 0.73(dq, J = 7.6, 2.4 Hz, 3H) ppm. (first eluting peak by SFC on ChiralpakIC column, rt = 1.84 min) 143rel-(2R,3S,4S,5R)-4-[[3-(3-methoxy-2-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 438.1515, found 440.1 (M+1)⁺; 437.2 (M-1)⁻; Retentiontime: 2.84 minutes ¹H NMR (500 MHz, Methanol-d4) δ 8.46 (d, J = 5.5 Hz,1H), 8.22 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 4.8, 1.3 Hz, 1H), 7.88 (dd,J = 5.5, 2.2 Hz, 1H), 7.38 (dd, J = 8.4, 1.4 Hz, 1H), 7.28 (dd, J = 8.3,4.8 Hz, 1H), 5.61 (d, J = 10.4 Hz, 1H), 4.39 (dd, J = (second elutingpeak by SFC on Chiralpak IC column, rt = 2.20 min) 10.4, 7.5 Hz, 1H),3.91 (s, 3H), 3.01 (p, J = 7.5 Hz, 1H), 1.62 (d, J = 1.5 Hz, 3H), 0.73(dq, J = 7.5, 2.3 Hz, 3H) ppm. 144rel-(2S,3R,4R,5S)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 452.16714, found 453.2 (M+1)⁺; 451.3 (M-1)⁻; Retentiontime: 2.64 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.68 (s, 1H), 8.50(d, J = 5.5 Hz, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.21 - 8.12 (m, 1H), 7.98(t, J = 1.6 Hz, 1H), 7.86 (s, 1H), 7.32 (s, 1H), 5.60 (s, 1H), 5.07 (d,J = 10.5 Hz, 1H), 4.22 (t, J = 9.5 Hz, 1H), 3.83 (d, J = 1.9 Hz, 3H),2.86 (p, J = 7.9 Hz, 1H), 2.68 (s, 3H), 1.72 (s, 3H), 0.94 - 0.74 (m,3H) ppm. (first eluting peak by SFC on Chiralcel OD-H column, rt = 4.26min) 145rel-(2R,3S,4S,5R)-4-[[3-(3-methoxy-2-methyl-4-pyridyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamideESI-MS m/z calc. 452.16714, found 453.3 (M+1)⁺; 451.3 (M-1)⁻; Retentiontime: 2.64 minutes ¹H NMR (500 MHz, Chloroform-d) δ 8.62 (s, 1H), 8.41(d, J = 5.5 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.04 (dd, J = 5.6, 2.2Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.76 (s, 1H), 7.31 (s, 1H), 5.52 (d,J = 4.4 Hz, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.14 (t, J = 9.5 Hz, 1H),3.76 (s, 3H), 2.79 (p, J = 7.9 Hz, 1H), 2.64 (s, 3H), 1.63 (s, 3H), 0.75(dt, J = 7.3, 2.4 Hz, 3H) ppm. (second eluting peak by SFC on ChiralcelOD-H column, rt = 5.04 min)

Example 284-[[(2r,3s,4s,5r)-3-[2-[(3,3-Difluorocyclobutyl)Methoxy]-3,4-Difluoro-Phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(146)

Step 1

To a stirred mixture of methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(13.5 g, 38.107 mmol) and potassium carbonate (6.85 g, 49.564 mmol) inN,N-dimethylformamide (50 mL) at room temperature, was added benzylbromide (9.7784 g, 6.8 mL, 57.172 mmol). The reaction mixture wasstirred overnight at room temperature. A further portion of benzylbromide (3.3074 g, 2.3 mL, 19.338 mmol) was added and the stirring wascontinued for 6 hrs. A further portion of potassium carbonate (2.6 g,18.812 mmol) and benzyl bromide (3.3074 g, 2.3 mL, 19.338 mmol) wereadded and reaction mixture was stirred overnight. The reaction mixturewas diluted with water (100 mL) and extracted with diethyl ether (3 ×100 mL). The combined organic extracts were washed with brine (50 mL),dried (Na₂SO₄), filtered and concentrated in vacuo. Purification byflash chromatography (SiO₂, 0 to 50% EtOAc in heptane) gave a 2:3mixture of methyl and benzyl(2S,3S,4S,5R)-3-(2-benzyloxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(12.2 g) as a yellow oil, which was used without further purification inthe next step.

Step 2

To a stirred mixture of 2:3 methyl and benzyl(2S,3S,4S,5R)-3-(2-benzyloxy-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.5 g, 1.3007 mmol) in 2-methyl tetrahydrofuran (5 mL), was addedpotassium tert-butoxide (438 mg, 3.9033 mmol) at 0° C. under argon. Thereaction mixture was stirred at 0° C. for 15 min then room temperaturefor 30 min. The reaction mixture was diluted with diethyl ether (20 mL)and acidified with aqueous hydrochloric acid (2 M solution). The aqueousphase was extracted with diethyl ether (20 mL) and the combined organicextracts were washed with brine (20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification by reverse phase chromatography(Biotage Isolera, 120 g, SiliaSep C18 Monomeric 25 µm Silicycle flashcartridge) using acetonitrile containing 0.1% ammonium hydroxide andwater containing 0.1% ammonium hydroxide (0:100 to 100:0) gave(2R,3S,4S,5R)-3-(2-benzyloxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (760 mg) as a white solid. ¹H NMR (400 MHz, chloroform-d) δ7.37-7.33 (m, 5H), 6.99-6.87 (m, 2H), 5.23 (d, J = 11.0 Hz, 1H), 5.07(d, J = 11.0 Hz, 1H), 4.83 (d, J = 11.0 Hz, 1H), 3.91 (dd, J = 11.0, 7.8Hz, 1H), 2.44 (dd, J = 15.3, 7.6 Hz, 1H), 1.37 (s, 3H), 0.66 (dd, J =7.3, 2.3 Hz, 3H) ppm; alcohol OH not observed. ESI-MS m/z calc.430.1204, found 429.04 (M-1)⁻.

Step 3

To a solution of(2R,3S,4S,5R)-3-(2-benzyloxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (3.3 g, 5.378 mmol) in ethyl acetate (20 mL) was added methyl4-aminopyridine-2-carboxylate (1.22 g, 8.018 mmol), TEA (2.24 mL, 16.07mmol) and T3P (6.4 mL, 21.52 mmol). The mixture was stirred at ambienttemperature for 4 hours. The reaction mixture was partitioned betweenethyl acetate (30ml) and water (60 ml). The organic layer was separatedand washed with water (1 × 50 ml) and brine (1 × 20 mL), dried (MgSO₄),filtered and concentrated in vacuo. Purification by flash chromatography(24 g pre-packed SiO₂, with 0-100% EtOAc/petroleum ether) gave theproduct methyl4-[[(2R,3S,4S,5R)-3-(2-benzyloxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(2.3 g, 65%) as an oil. ESI-MS m/z calc. 564.16833, found 565.1 (M+1)⁺.

Step 4

A mixture of methyl4-[[(2R,3S,4S,5R)-3-(2-benzyloxy-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(1.5 g, 2.438 mmol) and palladium on carbon 10% (75 mg, 0.705 mmol) inethanol (20 mL) was stirred under an atmosphere of hydrogen gas (1 atm,balloon) for 3.5 hrs. The reaction mixture was filtered through celiteand concentrated in vacuo to give a solid which was triturated withheptane, filtered and dried in vacuo. The solid was dissolved indichloromethane/methanol (9:1, 50 mL) and a saturated aqueous solutionof sodium hydrogencarbonate (50 mL). The aqueous phase was extractedwith dichloromethane/methanol (9:1, 2 × 50 mL). The combined organicextracts were washed with water (50 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The solid was triturated with heptane to givemethyl4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(1.07 g, 60%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (br s,1H), 10.82 (br s, 1H), 8.52 (d, J = 5.3 Hz, 1H), 8.29 (d, J = 1.5 Hz,1H), 7.78 (q, J = 2.5 Hz, 1H), 6.91 (s, 1H), 6.65 (s, 1H), 5.17 (d, J =9.9 Hz, 1H), 4.14 (t, J = 8.8 Hz, 1H), 3.83 (s, 3H), 2.81-2.72 (m, 1H),1.55 (s, 3H), 0.67 (d, J = 6.9 Hz, 3H) ppm. ESI-MS m/z calc. 474.1214,found 475.15 (M+1)⁺.

Step 5

To a solution of methyl4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(100 mg, 0.2108 mmol) in DMF (2 mL) was added1,1-difluoro-3-(iodomethyl)cyclobutane (244 mg, 1.052 mmol) and cesiumcarbonate (103 mg, 0.3161 mmol). The mixture was stirred at ambienttemperature for 48 hrs. The reaction mixture was partitioned betweenTBME (10ml) and water (10ml). The aqueous layer was further extractedwith TBME (10 mL). The combined organic fractions were washed with brine(1 × 10 mL), dried (MgSO₄), filtered and concentrated in vacuo to yieldthe crude product methyl4-[[(2R,3S,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(80 mg, 47%). ESI-MS m/z calc. 578.16516, found 579.2 (M+1)⁺.

Step 6

To a solution of methyl4-[[(2R,3S,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(80 mg, 0.1383 mmol) in methanol (1 mL) was added methanolic ammonia(500 µL of 7 M, 3.500 mmol) and the mixture stirred at ambienttemperature overnight. The mixture was concentrated in vacuo and theproduct was purified by reverse phase preparative (basic eluent) to give4-[[(2R,3S,4S,5R)-3-[2-[(3,3-difluorocyclobutyl)methoxy]-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(146, 39 mg, 49%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.50 (d, J= 5.5 Hz, 1H), 8.28 (d, J = 2.1 Hz, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.83(dd, J = 5.5, 2.2 Hz, 1H), 7.61 (d, J = 2.9 Hz, 1H), 7.23 - 7.16 (m,2H), 5.12 (d, J = 10.3 Hz, 1H), 4.26 (dt, J = 10.4, 6.5 Hz, 2H), 4.14(dd, J = 9.8, 6.5 Hz, 1H), 2.79 - 2.66 (m, 3H), 2.65 - 2.45 (m, 3H),1.61 (s, 3H), 0.76 - 0.64 (m, 3H) ppm. ESI-MS m/z calc. 563.1655, found564.2 (M+1)⁺.

Example 294-[[(2r,3s,4s,5r)-3-[2-(Cyclobutoxy)-3,4-Difluoro-Phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(147)

Step 1 and 2

To a solution of methyl(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(200 mg, 0.5645 mmol) in a mixture of MeCN (2 mL) and DMF (1 mL) wasadded K₂CO₃ (250 mg, 1.809 mmol) and bromocyclobutane (200 mg, 1.481mmol). The mixture was heated to 75° C. in a sealed vial for 90 min.Upon completion the mixture was diluted with DCM and partitioned withwater. The organic phase was dried (MgSO₄), filtered and concentrated invacuo. Purification by flash chromatography gave methyl(2R,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(70 mg, 30%). This was immediately taken in THF (1 mL) and potassiumtert-butoxide (60 mg, 0.5347 mmol) was added at ambient temperature. Themixture is diluted with DCM (10 mL) and partitioned with a saturatedsolution of ammonium chloride (10 mL). The organics were separated,dried (MgSO₄), filtered and concentrated in vacuo to give(2R,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (50 mg, 22%), which was used without further purification. ESI-MSm/z calc. 394.12036, found 393.5 (M-1)⁻.

Step 3 and 4

Oxalyl chloride (30 µL, 0.3439 mmol) was added dropwise to a stirredsolution of(2R,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (50 mg, 0.1268 mmol) and DMF (2 µL, 0.02583 mmol) in DCM (500 µL)at ambient temperature. The mixture was stirred for 30 min. Uponcomplete acid chloride formation, the solution was concentrated in vacuoand the residue dissolved in DCM (300 µL). The obtained solution wasadded to a stirred solution of methyl 4-aminopyridine-2-carboxylate (25mg, 0.1643 mmol) and TEA (30 µL, 0.2152 mmol) in DCM (300 µL) at ambienttemperature and allowed to stir for 2 hrs. The mixture was quenched with100 µL of methanol and purified by flash chromatography to afford methyl4-[[(2R,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(30 mg, 45%). ESI-MS m/z calc. 528.16833, found 527.6 (M+1)⁺.

The residue was taken up in methanolic ammomia (4 mL of 7 M, 28.00 mmol)and stirred at ambient temperature until complete conversion.Purification by flash chromatography gave4-[[(2R,3S,4S,5R)-3-[2-(cyclobutoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(147, 13 mg, 17%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.73 (s, 1H), 8.49 (d, J= 5.5 Hz, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.82(dd, J = 5.5, 2.2 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.15 (t, J = 6.4 Hz,2H), 5.09 (d, J = 10.4 Hz, 1H), 4.65 (p, J = 7.3 Hz, 1H), 4.28 (dd, J =10.5, 7.5 Hz, 1H), 2.77 (h, J = 7.8 Hz, 1H), 2.36 - 2.22 (m, 2H), 2.14(ddt, J = 35.2, 19.5, 10.2 Hz, 2H), 1.70 (dd, J = 11.7, 9.0 Hz, 1H),1.62 (s, 3H), 1.48 (dtd, J = 18.2, 10.3, 7.8 Hz, 1H), 0.72 (d, J = 7.1Hz, 3H) ppm. ESI-MS m/z calc. 513.1687, found 514.6 (M+1)⁺and 512.5(M-1)⁻.

Example 304-[[(2r,35,45,5r)-3-(5-Deuterio-3,4-Difluoro-2-Methoxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(148)

Step 1

DMSO (80 µL, 1.127 mmol) and NIS (1.7 g, 7.556 mmol) were added to astirred solution of methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(2.2 g, 6.210 mmol) in MeOH (20 mL) at ambient temperature. The mixturewas stirred at ambient temperature under air for 30 min. Uponcompletion, the mixture was concentrated in vacuo. Purification by flashchromatography gave methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-5-iodo-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(2.78 g, 93%). ¹H NMR (500 MHz, Chloroform-d) δ 7.49 (dt, J = 6.4, 2.1Hz, 1H), 5.56 (d, J = 4.9 Hz, 1H), 4.81 (d, J = 5.9 Hz, 1H), 4.16 (dd, J= 8.3, 5.9 Hz, 1H), 3.60 (s, 3H), 2.75 (p, J = 7.7 Hz, 1H), 1.45 (d, J =1.2 Hz, 3H), 0.90 - 0.85 (m, 3H) ppm. ESI-MS m/z calc. 479.9857, found481.1 (M+1)⁺ and 479.1 (M-1)⁻.

Step 2

K₂CO₃ (2.5 g, 18.09 mmol) and MeI (1 mL, 16.06 mmol) were added to asolution of methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-5-iodo-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(2.8 g, 5.831 mmol) in MeCN (25 mL). The mixture was heated to 75° C. ina sealed vial for 90 min. The mixture was diluted in DCM and partitionedwith an aqueous saturated solution of NaCl. The organic extracts weredried (MgSO₄), filtered and concentrated in vacuo to afford methyl(2S,3S,4S,5R)-3-(3,4-difluoro-5-iodo-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(2.8 g, 97%). ¹H NMR (500 MHz, Chloroform-d) δ 7.53 (dq, J = 6.5, 1.5Hz, 1H), 4.80 (d, J = 6.1 Hz, 1H), 4.11 (dd, J = 8.5, 5.8 Hz, 1H), 3.88(d, J = 2.4 Hz, 3H), 3.56 (s, 3H), 2.73 (p, J = 8.4, 7.8 Hz, 1H), 1.45(d, J = 1.1 Hz, 3H), 0.80 (dd, J = 7.4, 1.9 Hz, 3H) ppm. ESI-MS m/zcalc. 494.00134, found 495.2 (M+1)⁺.

Step 3

iPrMgCl.LiCl (100 µL of 1.3 M, 0.1300 mmol) was added dropwise to astirred solution of methyl(28,35.45,5R)-3-(3,4-difluoro-5-iodo-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(70 mg, 0.1416 mmol) in THF (1.5 mL) at -78° C. The resulting mixturewas stirred at -78° C. for 10 min. The resulting mixture was quenched at-78° C. with a solution of D₂O (0.1 mL, 5.542 mmol) in THF (1.5 mL). Thereaction mixture was allowed to warm up to ambient temperature, dilutedwith DCM and partitioned with brine. The organic layer was separated,dried (MgSO₄), filtered and concentrated in vacuo to afford methyl(2S,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(43 mg, 82%). ¹H NMR (500 MHz, Chloroform-d) δ 7.16 (d, J = 5.8 Hz, 1H),4.87 (d, J = 6.1 Hz, 1H), 4.23 (dd, J = 8.6, 6.1 Hz, 1H), 3.94 (d, J =2.0 Hz, 3H), 3.54 (s, 3H), 2.82 (p, J = 7.8 Hz, 1H), 1.53 (s, 3H), 0.86(dt, J = 7.6, 1.9 Hz, 3H) ppm.

Step 4

Potassium tert-butoxide (120 mg, 1.069 mmol) was added to a stirredsolution of methyl(25,35,45,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(100 mg, 0.2708 mmol) in THF (1.5 mL) at room temperature. After 5minutes, the mixture was quenched by the addition of a saturatedsolution of ammonium chloride (3 mL) and diluted with DCM (3 mL). Theaqueous phase was washed with DCM (5 mL), acidified with 1 N HC1 to pH 0and extracted with DCM (2 × 10 mL). The combined organic extracts weredried (MgSO₄), filtered and concentrated in vacuo to afford(2R,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (95 mg, 99%), which was used in the next step without furtherpurification. ESI-MS m/z calc. 355.09534, found 354.2 (M-1)⁻.

Step 5 and 6

Oxalyl chloride (70 µL, 0.8024 mmol) was added dropwise to a stirredsolution of(2R,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (90 mg, 0.2533 mmol) and DMF (3 µL, 0.03874 mmol) in DCM (1000 µL)at ambient temperature. The mixture was stirred at room temperature for30 min. Upon activation completion, the mixture was concentrated invacuo and re-dissolved in DCM (500 µL). This obtained solution was addedto a stirring solution of methyl 4-aminopyridine-2-carboxylate (50 mg,0.3286 mmol) and triethylamine (50 µL, 0.3587 mmol) in DCM (500 µL) atambient temperature. Upon complete conversion, the mixture was quenchedwith 0.1 mL of MeOH. Purification by flash chromatography gave methyl4-[[(2R,35,45,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(31 mg, 25%), which was used as is in the next step. ESI-MS m/z calc.489.14334, found 490.4 (M+1)⁺; 488.4 (M-1)⁻.

Methyl4-[[(2R,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(31 mg) was taken in a methanolic solution of ammonia (8.5 mL of 7 M,59.50 mmol) and stirred at ambient temperature until complete conversionto the corresponding amide. The final compound was lyophilized fromMeCN:Water 3:1 to provide4-[[(2R,3S,4S,5R)-3-(5-deuterio-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide(148, 17.4 mg, 14%, 93% isotopic purity for D). ¹H NMR (500 MHz,DMSO-d₆) δ 10.70 (s, 1H), 8.49 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 2.2 Hz,1H), 8.05 (s, 1H), 7.83 (dd, J = 5.6, 2.2 Hz, 1H), 7.60 (s, 1H), 7.17 -7.12 (m, 1H), 5.10 (d, J = 10.2 Hz, 1H), 4.26 (dd, J = 10.2, 7.7 Hz,1H), 3.95 (d, J = 2.0 Hz, 3H), 2.77 (p, J = 7.5 Hz, 1H), 1.61 (s, 3H),0.73 (d, J = 7.4 Hz, 3H) ppm. ESI-MS m/z calc. 474.14368, found 475.4(M+1)⁺; 473.4 (M-1)⁻.

Example 314-[[(2r,3s,4s,5r)-3-(3,4-Difluoro-2-Vinyl-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(149)

Step 1

To a solution of methyl(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.3 g, 3.670 mmol) in methanol (5 mL) was added methanolic ammonia (10mL of 7 M, 70.00 mmol) and the mixture was stirred at ambienttemperature for 14 hours. The mixture was concentrated in vacuo to give(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(1.2 g, 87%) as a white solid. ESI-MS m/z calc. 339.0894, found 340.2(M+1)⁺.

Step 2

To a solution of(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(1.2 g, 3.537 mmol) in DCM (10 mL) cooled with an ice-bath was addedpyridine (572 µL, 7.072 mmol) followed by trifluoromethylsulfonyltrifluoromethanesulfonate (4.59 mL of 1 M, 4.590 mmol) in portions over5 mins. The reaction mixture was allowed to warm up to ambienttemperature and was partitioned between DCM (20 ml) and water (20 ml).The organic phase was washed with brine (1 × 10 mL), dried (MgSO₄),filtered and concentrated in vacuo. Purification by flash chromatography(12 g SiO₂, 0 to 100% EtOAc in heptane) gave[6-[(2R,3S,4S,5R)-2-carbamoyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-3-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate (1.2 g, 72%) as a white solid. ESI-MS m/zcalc. 471.03867, found 472.2 (M+1)⁺.

Step 3

A mixture of[6-[(2R,3S,4S,5R)-2-carbamoyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-3-yl]-2,3-difluoro-phenyl]trifluoromethanesulfonate (200 mg, 0.4243 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (130 mg, 0.8441 mmol),cesium carbonate (276 mg, 0.8471 mmol) and RuPhos-Pd-G3 (35 mg, 0.04185mmol) was suspended in toluene (2 mL) and water (0.2 mL). The suspensionwas degassed (N₂/vac 3 cycles) and heated to 80° C. for 5 hours. Thereaction mixture was cooled down to ambient temperature and partitionedbetween TBME (20 ml) and water (20 ml). The aqueous layer was furtherextracted with TBME (10 mL). The combined organic extracts were washedwith brine (1 × 10 mL), dried (MgSO₄), filtered and concentrated invacuo. Purification by flash chromatography (12 g SiO₂, 0 to 100% EtOAcin heptane) gave(2R,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(50 mg, 30%) as a white solid. ¹H NMR (500 MHz, Chloroform-d) δ 7.13(ddd, J = 17.3, 8.3, 3.3 Hz, 2H), 6.63 -6.51 (m, 2H), 5.75 - 5.63 (m,3H), 4.94 (d, J = 10.6 Hz, 1H), 3.99 (dd, J = 10.7, 8.1 Hz, 1H), 2.62(p, J = 7.7 Hz, 1H), 1.61 (s, 3H), 0.76 (d, J = 7.6 Hz, 3H) ppm. ESI-MSm/z calc. 349.1101, found 350.2 (M+1)⁺.

Step 4

Methyl 4-bromopyridine-2-carboxylate (35 mg, 0.1620 mmol), Xantphos (20mg, 0.03457 mmol), cesium carbonate (85 mg, 0.2609 mmol), Pd(OAc)₂ (4mg, 0.01782 mmol) and(2R,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(30 mg, 0.08589 mmol) were combined in dioxane (3 mL). The suspensionwas degassed (N₂/vac 3 cycles) and heated at 90° C. under nitrogen for 4hours. The reaction mixture was cooled down to ambient temperature andpartitioned between TBME (10 ml) and water (10 ml). The aqeuous layerwas further extracted with TBME (10 mL). The combined organic layerswere washed with brine (1 × 10 mL), dried (MgSO₄), filtered andconcentrated in vacuo. Purification by column chromatography (12 g SiO₂,0 to 100% EtOAc in heptane gave methyl4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(20 mg, 47%) as a white solid. ESI-MS m/z calc. 484.14215, found 485.4(M+1)⁺.

Step 5

To a solution of methyl4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylate(8 mg, 0.01651 mmol) in methanol (1 mL) was added methanolic ammonia(235 µL of 7 M, 1.645 mmol) and the mixture was stirred at ambienttemperature for 14 hours. The mixture was concentrated in vacuo.Purification by reverse phase preparative HPLC (Waters Sunfire C18, 10µM, 100 Å column, gradient 0% - 100% B (solvent A: 0.1% NH₃ in water;solvent B: MeCN) over 14 minutes at 25 mL/min) gave4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-vinyl-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide149 (2.5 mg, 31%). ¹H NMR (500 MHz, Methanol-d₄) δ 8.50 (dd, J = 5.5,0.6 Hz, 1H), 8.26 (dd, J = 2.2, 0.6 Hz, 1H), 7.91 (dd, J = 5.5, 2.2 Hz,1H), 7.24 - 7.13 (m, 2H), 6.76 (dd, J = 17.8, 11.6 Hz, 1H), 5.81 - 5.64(m, 2H), 5.14 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 10.4, 8.0 Hz, 1H),2.77 (p, J = 7.7 Hz, 1H), 1.66 (d, J = 1.2 Hz, 3H), 0.82 (dq, J = 7.4,2.3 Hz, 3H) ppm. ESI-MS m/z calc. 469.1425, found 470.4 (M+1)⁺.

4-[[(2R,3S,4S,5R)-3-(2-ethyl-3,4-difluoro-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamidecan be obtained by hydrogenation of compound 149 (e.g., Pd/C, H₂).

Example 32Rel-(2r,3s,4s,5r)-4-[[3-[2-(Difluoromethoxy)-3,4-Difluoro-Phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]-5-Methyl-Pyridine-2-Carboxamide(150) andRel-(2s,3r,4r,5s)-4-[[3-[2-(Difluoromethoxy)-3,4-Difluoro-Phenyl]-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]-5-Methyl-Pyridine-2-Carboxamide(151)

Step 1

To an ice cooled solution ofrac-(2R,3S,4S,5R)-3-[2-(difluoromethoxy)-3,4-difluorophenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (90 mg, 0.2306 mmol) (see Example 4, Step 1) in DCM (1.2 mL) wasadded oxalyl chloride (45 µL, 0.5159 mmol) and the mixture was stirredand warmed up to room temperature over 30 min after which time fullconversion to acid chloride was observed. The reaction mixture wasconcentrated in vacuo. The residue, dissolved in DCM (750 µL) and DMF (8µL, 0.1033 mmol) was added to an ice cooled solution of2-bromo-5-methyl-pyridin-4-amine (46 mg, 0.2459 mmol) and TEA (40 µL,0.2870 mmol) in DCM (750 µL). The resulting mixture was stirred andwarmed to ambient temperature over 2 hours. The reaction mixture wasquenched with 1 drop of water and MeOH (2 mL) and concentrated in vacuo.Purification by flash chromatography (4 g SiO₂, 0 to 100 % EtOAc inhexames) gaverac-(2R,3S,4S,5R)-N-(2-bromo-5-methyl-4-pyridyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(55 mg, 43%). ESI-MS m/z calc. 558.0389, found 561.4 (M+1)⁺; 559.5(M-1)⁻.

Step 2 and 3

A suspension ofrac-(2R,3S,4S,5R)-N-(2-bromo-5-methyl-4-pyridyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide(50 mg, 0.08940 mmol), Pd(dppf)Cl₂·DCM (7 mg, 0.008572 mmol) and TEA (30µL, 0.2152 mmol) in DMF (700 µL) and MeOH (300 µL). CO was bubbledthrough the reaction mixture, the vessel sealed and heated to 80° C. for20 hours. The reaction mixture was concentrated in vacuo to give methylrac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxylate,which was used as is in the next step. ESI-MS m/z calc. 538.13385, found539.6 (M+1)⁺; 537.7 (M-1)⁻.

Methylrac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxylate(40 mg, 0.07429 mmol) was taken in a methanolic solution of ammonia (2.4mL of 7 M, 16.80 mmol) in MeOH (2.4 mL). The mixture was stirred atambient temperature. Upon completion, the mixture was concentrated invacuo. Purification by flash chromatography gaverac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(22 mg, 57% over 2 steps). ESI-MS m/z calc. 523.1342, found 524.5(M+1)⁺; 522.6 (M-1)⁻.

Step 4

rac-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(20 mg, 0.038 mmol) was separated by chiral SFC using a Chiralpak AS-Hcolumn, 5 µm particle size, 25 cm x 10 mm from Daicel on a Minigram SFCinstrument from Berger Instruments to give:

First Eluting Isomer (rt = 2.12 min):rel-(2R,3S,4S,5R)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methyl-pyridine-2-carboxamide(150, 9 mg, 44%). ¹H NMR (400 MHz, Methanol-d₄) δ 8.51 - 8.42 (m, 2H),7.46 - 7.36 (m, 1H), 7.29 (td, J = 9.4, 7.6 Hz, 1H), 6.95 (td, J = 73.1,1.2 Hz, 1H), 5.23 (d, J = 10.8 Hz, 1H), 4.35 (dd, J = 10.8, 7.9 Hz, 1H),2.86 (p, J = 7.6 Hz, 1H), 2.31 (s, 3H), 1.72 (d, J = 1.1 Hz, 3H), 0.89(dq, J = 7.5, 2.4 Hz, 3H) ppm. ESI-MS m/z calc. 523.1342, found 524.4(M+1)⁺; 522.4 (M-1)⁻.

Second Eluting Isomer (rt = 3.44 min):rel-(2S,3R,4R,5S)-4-[[3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]-5-methylpyridine-2-carboxamide(151, 7 mg, 35%). ¹H NMR (400 MHz, Methanol-d₄) δ 8.54 - 8.42 (m, 2H),7.41 (ddd, J = 9.0, 5.4, 2.3 Hz, 1H), 7.29 (td, J = 9.4, 7.6 Hz, 1H),6.95 (td, J = 73.0, 1.1 Hz, 1H), 5.23 (d, J = 10.8 Hz, 1H), 4.35 (dd, J= 10.8, 7.9 Hz, 1H), 2.86 (p, J = 7.6 Hz, 1H), 2.31 (s, 3H), 1.72 (d, J= 1.1 Hz, 3H), 0.89 (dq, J = 7.5, 2.4 Hz, 3H) ppm. ESI-MS m/z calc.523.1342, found 524.4 (M+1)⁺; 522.4 (M-1)⁻.

Example 334-[[(2r,3s,4s,5r)-3-(5-Chloro-3,4-Difluoro-2-Methoxy-Phenyl)-4,5-Dimethyl-5-(Trifluoromethyl)Tetrahydrofuran-2-Carbonyl]Amino]Pyridine-2-Carboxamide(152)

Step 1

NCS (1 g, 7.489 mmol) and DMSO (80 µL, 1.127 mmol) were added to asolution of methyl(2S,3S,4S,5R)-3-(3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(2 g, 5.645 mmol) in MeOH (18 mL) at room temperature and under air. Themixture was stirred until complete conversion. The reaction mixture wasconcentrated in vacuo. Purification by flash chromatography gave methyl(2S,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(2.05 g, 93%). ¹H NMR (500 MHz, Chloroform-d) δ 7.23 - 7.19 (m, 1H),5.44 (d, J = 4.8 Hz, 1H), 4.81 (d, J = 5.9 Hz, 1H), 4.19 (dd, J = 8.4,5.8 Hz, 1H), 3.57 (s, 3H), 2.81 - 2.71 (m, 1H), 1.46 (d, J = 1.3 Hz,3H), 0.90 - 0.85 (m, 3H) ppm. ESI-MS m/z calc. 388.05008, found 386.9(M-1)⁻.

Step 2

Potassium carbonate (2 g, 14.47 mmol) and iodomethane (650 µL, 10.44mmol) were added to a mixture of methyl(2S,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-hydroxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.9 g, 4.888 mmol) in MeCN (20 mL) in a sealed tube. The mixture washeated to 75° C. for 2h. The mixture was diluted with water/brine 1:1(20 mL) and extracted with DCM. The organic extracts were dried (MgSO₄),filtered and concentrated in vacuo. Purification by flash chromatographygave methyl(2S,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(1.85 g, 94%) as a yellow crystalline solid. ¹H NMR (500 MHz,Chloroform-d) δ 7.30 (ddq, J = 7.6, 3.0, 1.6 Hz, 1H), 4.87 (d, J = 5.9Hz, 1H), 4.21 (dd, J = 8.6, 6.0 Hz, 1H), 3.94 (d, J = 2.1 Hz, 3H), 3.61(s, 3H), 2.82 (p, J = 7.8 Hz, 1H), 1.52 (d, J = 1.3 Hz, 3H), 0.87 (dq, J= 7.7, 2.0 Hz, 3H) ppm.

Step 3

Potassium tert-butoxide (450 mg, 4.010 mmol) was added to a stirredsolution of methyl(2S,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate(800 mg, 1.986 mmol) in THF (40 mL) at 0° C. The mixture was stirreduntil complete conversion. The reaction mixture was quenched by additionof a saturated solution of ammonium chloride (3 mL) and partitioned withDCM (3 mL). The aqueous phase extracted with DCM (5 mL), and the pH wasadjusted to 0 by addition of a 1 N solution of HCl. The aqueous phasewas extracted twice with DCM (2 × 10 mL). The combined organic extractswere dried (MgSO₄), filtered and concentrated concentrated in vacuo togive(2R,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid, which was used in the next step without further purification.ESI-MS m/z calc. 388.05008, found 386.9 (M-1)⁻.

Step 4 and 5

Oxalyl chloride (130 µL, 1.490 mmol) was added dropwise to a stirredsolution of(2R,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylicacid (250 mg, 0.643 mmol) and DMF (7 µL, 0.090 mmol) in DCM (2.5 mL).The reaction mixture was stirred at ambient temperature for 30 min. Thesolution was concentrated in vacuo. The residue was dissolved in DCM(1.5 mL) and added to a solution of methyl 4-aminopyridine-2-carboxylate(130 mg, 0.8544 mmol) and TEA (130 µL, 0.9327 mmol) in DCM (1.5 mL) atambient temperature. The reaction mixture was stirred for 2h. Themixture was quenched by addition of methanol (100 µL). Purification byflash chromatography gave methyl4-[[(2R,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylatewhich was used in the next step without further purification. ESI-MS m/zcalc. 522.0981, found 523.0 (M+1)⁺;521.0 (M-1)⁻.

Methyl4-[[(2R,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxylatewas taken in a methanolic solution of ammonia (20 mL of 7 M, 140.0 mmol)and stirred at ambient temperature. Upon completion, the mixture wasconcentrated in vacuo and freeze-dried (MeCN:water, 3:1) to give4-[[(2R,3S,4S,5R)-3-(5-chloro-3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide152 (45 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.50 (d, J= 5.5 Hz, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 3.0 Hz, 1H), 7.86(dd, J = 5.6, 2.3 Hz, 1H), 7.62 (d, J = 3.0 Hz, 1H), 7.42 (dd, J = 7.7,2.4 Hz, 1H), 5.18 (d, J = 9.9 Hz, 1H), 4.24 (dd, J = 10.1, 7.6 Hz, 1H),3.97 (d, J = 2.4 Hz, 3H), 2.78 (p, J = 7.4 Hz, 1H), 1.62 (s, 3H), 0.76(dd, J = 7.6, 2.2 Hz, 3H) ppm. ESI-MS m/z calc. 507.09842, found 508.0(M+1)⁺;506.1 (M-1)⁻.

Intermediate A 3,3-Difluorobutan-2-One

Step 1

To a stirred solution of 2,2-difluoropropanoic acid (100 g, 908.60 mmol)in DCM (1000 mL) was added DIPEA (348.74 g, 470 mL, 2.6983 mol) at 25°C. The reaction mixture was stirred for 15 minutes. EDC.HCl (209 g,1.0902 mol) and HOBt (147 g, 1.0879 mol) were added and the reactionmixture was stirred for 15 minutes at 25° C. N,O-Dimethylhydroxylaminehydrochloride (133 g, 1.3635 mol) was added to the reaction which wasstirred for 16 hrs. Water was added and the mixture was extracted withDCM (2 × 200 ml ). The combined organic layers were washed with water (2× 200 ml) and brine (200 ml). Purification by distillation under vacuo(192-196° C.) gave 2,2-difluoro-N-methoxy-N-methyl-propanamide (70.5 g,51%) as a colourless oil. ¹H NMR (400 MHz, Chloroform-d) δ 3.72 (s, 3H),3.24 (s, 3H), 1.81 (t, J = 19.20 Hz, 3H) ppm.

Step 2

MeMgBr (1:3 THF in toluene) (489 mL of 1.4 M, 684.60 mmol) was slowlyadded dropwise to a stirred solution of2,2-difluoro-N-methoxy-N-methyl-propanamide (70 g, 457.14 mmol) intoluene (350 mL) at -78° C. The reaction mixture was stirred for 2 hoursat -78° C. The mixture was quenched by addition of HCl (685 mL of 2 M,1.3700 mol) at 0° C. Cold water was added. The organic layer was washedwith water. Purification by distillation (100° C.) gave3,3-difluorobutan-2-one (26.3 g, 53%). ¹H NMR (400 MHz, Chloroform-d) δ2.33 (s, 3H), 1.69 ( t, J = 19.12 Hz, 3H) ppm.

Intermediate B2-(Difluoromethoxy)-4-Fluoro-Phenyl]-4,4,5,5-Tetramethyl-1,3,2-Dioxaborolane

Step 1

1-Bromo-2-(difluoromethoxy)-4-fluoro-benzene (10 g, 41.49 mmol),bis(pinacol)diboron (11.00 g, 43.32 mmol) and Potassium acetate (12.00g, 122.3 mmol) were mixed in dry DMF (100 mL). The mixture was degassed(Vac/N₂ 3 cycles). Pd(dppf)Cl₂·DCM (3.4 g, 4.163 mmol) was added, andthe reaction mixture was degassed (Vac/N₂ 3 cycles). The reactionmixture was heated to 110° C. for 18 hours. The reaction mixture wasdiluted with water (300 mL) and EtOAc (150 mL), stirred for 30 min,filtered through a pad of celite, washing with EtOAc. The organic phasewas separated and washed with water (2 ×150 ml) and brine (2 × 150 ml),dried (MgSO₄), filtered and concentrated in vacuo. Purification on a padof florisil (200 g, 0 to 10% DCM in hexanes) gave2-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(8.43 g, 71%) as a yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ 7.71 (dd, J =8.4, 7.3 Hz, 1H), 7.28-7.96 (m, 3 H), 1.28 (s, 12 H); ¹⁹F NMR (471 MHz,DMSO-d₆) δ -82.70 (d, J = 74.5 Hz), -106.63 (s) ppm.

The following intermediates were made using a method similar to thatdescribed in Intermediate B except that 1,4-dioxane was used as thesolvent in place of DMF:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) M2-[2-(difluoromethoxy)-4-fluoro-3-methyl-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane¹H NMR (400 MHz, DMSO-d₆) δ 7.57 ( t, J=7.76 Hz, 1H ), 7.17 (t, J=8.72Hz, 1H), 6.95 (t, J= 75.08 Hz, 1H) 2.16 (s, 3H) 1.32 (s, 12H) ppm. N4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine

Intermediate C2-(Difluoromethyl)-4-Fluoro-2-Methoxyphenyl)-4,4,5,5-Tetramethyl-1,3,2-Dioxaborolane

Step 1

To a solution of 1-bromo-3-(difluoromethyl)-4-fluoro-2-methoxy-benzene(1.60 g, 6.274 mmol) and Pd(PPh₃)₂Cl₂ (200 mg, 0.2849 mmol) in1,4-dioxane (25 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.6 mL, 11.03 mmol) and TEA (2.5 mL, 17.94 mmol). The mixture wasdegassed by bubbling nitrogen through for 5 minutes. The reaction washeated at 100° C. in a sealed vial for 3 hours. The reaction wasconcentrated in vacuo and loaded onto solid support. Purification byflash chromatography (0 to 25 % EtOAc in heptane) gave2-[3-(difluoromethyl)-4-fluoro-2-methoxy-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.15 g, 53%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 7.84(ddt, J = 8.2, 6.9, 1.2 Hz, 1H), 6.99 (td, J = 53.9, 1.1 Hz, 1H), 6.91(dd, J = 9.7, 8.5 Hz, 1H), 3.90 (s, 3H), 1.36 (s, 12H). ESI-MS m/z calc.302.1301, Retention time: 1.03 minutes.

Intermediate D2-Chloro-4-Fluoro-2-Methoxyphenyl)-4,4,5,5-Tetramethyl-1,3,2-Dioxaborolane

Step 1

An oven dried 500 ml three necked flask was flanked with a condenser anda thermometer. Magnesium (321 mg, 13.21 mmol) turnings were added. Theflask was evacuated three times with vac/N₂ and then left under vacuumfor thirty minutes while the flask was heated to 65° C. Using a nitrogenflushed needle, THF (12.5 mL) was added to the flask and the mixture wasflushed once again with nitrogen. Iodine (3 mg, 0.01182 mmol) was addedto the reaction. The mixture was stirred at 65° C. until the reactionturned into a clear pale yellow colour (~1 hour). The mixture was takenoff the heat. Pinacolborane (1.74 g, 13.60 mmol) was added dropwise. Gasevolution was observed. A solution of1-bromo-3-chloro-4-fluoro-2-methoxy-benzene (2500 mg, 10.44 mmol) in THF(12.5 mL) was added dropwise. The reaction mixture was left to cool toambient temperature over 30 minutes and stirred for 1.5 h at ambienttemperature. The reaction mixture was added carefully dropwise to astirred solution of 1 M HCl (50 ml) (vigorous effervescence observed)and left to stand for 10 minutes until all the Mg solids had dissolved.The mixture was diluted with TBME. The aqueous layer was separated andextracted with TBME (x2), passed through a phase separator cartridge andconcentrated in vacuo to give2-(3-chloro-4-fluoro-2-methoxy-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.8152 g, 94%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.57 (dd, J = 8.4, 7.0 Hz,1H), 7.24 - 7.15 (m, 1H), 3.81 (s, 3H), 1.30 (s, 12H). ESI-MS m/z calc.286.09433, found 287.0 (M+1)+; Retention time: 1.06 minutes.

The following intermediate was made using a method similar to thatdescribed in Intermediate D using1-bromo-4-fluoro-2-methoxy-3-methyl-benzene as starting material:

Cmpd No. Compound Name LC/MS NMR (shifts in ppm) O2-(4-fluoro-2-methoxy-3-methyl-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane¹H NMR (400 MHz, DMSO-d₆) δ 7.44 (t, J = 7.9 Hz, 1H), 6.93 (t, J = 8.7Hz, 1H), 3.72 (s, 3H), 2.11 (d, J = 2.1 Hz, 3H), 1.29 (s, 12H) ppm. ¹⁹FNMR (376 MHz, DMSO-d₆) δ -110.32 (ddt, J = 9.5, 7.3, 2.2 Hz) ppm.

Intermediate E Fluoro-2-Methoxy-3-Methylphenyl)Boronic Acid

Step 1

Isopropylamine (23.460 g, 34.5 mL, 396.89 mmol) was slowly added to astirred solution of 3-fluoro-2-methyl-phenol (50 g, 396.42 mmol) in DCM(2.5 L). The reaction mixture was cooled to -78° C. N-bromosuccinimide(NBS) (70 g, 393.29 mmol) was added portion wise over 2 hrs 10 min andthe mixture was stirred for a further 30 min. The mixture was warmed upto 25° C. 2N HCl (500 ml) was added and the mixture was stirred for 15min. The organic layer was separated and concentrated in vacuo, keepingthe water bath at 15° C. Hexane (500 ml) was added to the residue andthe mixture was stirred for 10 min. The mixture was filtered and theliquors were concentrated in vacuo, keeping the water bath at 15° C. togive 6-bromo-3-fluoro-2-methyl-phenol (73 g, 90%) as a light brown oil.¹H NMR (400 MHz, Chloroform-d) δ 7.24-7.21 (m, 1H), 6.55 (t, J = 8.8 Hz,1H), 5.61 (s, 1H), 2.20 (s, 3H) ppm.

Step 2

To a stirred solution of 6-bromo-3-fluoro-2-methyl-phenol (40 g, 195.10mmol) in acetone (400 mL) at ambient temperature was added potassiumcarbonate (135 g, 976.80 mmol). The reaction mixture was stirred for 10min at 25° C. Methyl iodide (39 g, 17.105 mL, 274.77 mmol) was addeddropwise over 10 min and the mixture was stirred for 16 hrs at 25° C.The reaction mixture was filtered and the solid residues washed withacetone (50 ml). The mother liquors were concentrated at 15° C. underreduced pressure. Hexane (200 ml) was added and the mixture was stirredfor 15 minutes. The solid was collected and washed with hexane (8 ml).The mother liquors were concentrated under reduced pressure at 15° C.Purification by distillation (520 mm Hg, 192-196° C.) gave1-bromo-4-fluoro-2-methoxy-3-methyl-benzene (32.4 g, 76%). ¹H NMR (400MHz, Chloroform-d) δ 7.33-7.30 (m, 1H), 6.72 (t, J = 8.7 Hz, 1H), 3.80(s, 3H), 2.23 (s, 3H) ppm.

Step 3

Iodine (50 mg, 0.1970 mmol) was added at 25° C. to a stirred mixture ofMg turnings (5 g, 205.72 mmol) in THF (50 ml). The mixture was stirreduntil the reaction turned into a clear pale yellow colour.1-bromo-4-fluoro-2-methoxy-3-methyl-benzene (2.5 g, 11.4 mmol) was addeddropwise at ambient temperature. When reaction initiation was observed,the remaining solution of 1-bromo-4-fluoro-2-methoxy-3-methyl-benzene(22.5 g,102.71 mmol) in THF (200 ml) was added dropwise. The mixture wasstirred for 40 minutes. Reaction was cooled down to -78° C. andtriisopropylborate (64.385 g, 79 mL, 342.34 mmol) was added dropwise.The mixture was warmed up to ambient temperature and stirred for 16 hrs.The reaction was quenched by addition of a 2N aqueous solution of HCl(25 ml) and stirred for 15 minutes. The mixture was diluted with water(125 ml) and extracted with ethyl acetate (2 × 250 ml). The organiclayer was separated, washed with water (250 ml), dried (Na₂SO₄) andconcentrated in vacuo. Hexane (2 5 ml) was added to the residue at 0° C.and the mixture was stirred for 5 minutes. The resulting solid wasfiltered, washed with 10 ml of chilled hexane and dried to give(4-fluoro-2-methoxy-3-methyl-phenyl)boronic acid (11.5 g, 55%). ¹H NMR(400 MHz, DMSO-d₆) δ 7.96 (br s, 2H), 7.32 (t, J = 8.0 Hz, 1H ), 6.88(t, J = 8.7 Hz, 1H), 3.75 (s, 3H), 2.11 (s, 3H) ppm.

Intermediate F 1-BromoEthyl-4-Fluoro-2-Methoxy-Benzene

Step 1

Pd(dppf)Cl₂.DCM (7.5 g, 9.1840 mmol) was added to a stirred mixture of2-bromo-3-fluoro-phenol (25 g, 130.89 mmol), potassiumvinyltrifluoroborate (52 g, 388.20 mmol) and K₂CO₃ (55 g, 397.96 mmol)in a mixture of 1,4-dioxane (250 mL) and water (25 mL). The mixture wasdegassed by bubbling through nitrogen gas for 15 minutes. The mixturewas heated to 90° C. for 16 h. The reaction mixture was filtered througha pad of celite. The collected mother liquors were diluted with water(300 mL). The aqueous phase was extracted with EtOAc (2 × 50 mL). Thecombined organic extracts were dried (MgSO₄), filtered and concentratedin vacuo. Purification by flash chromatography (SiO₂, 0-1 % EtOAc inhexanes) gave 3-fluoro-2-vinyl-phenol (14.5 g, 72%) as a colourless oil.¹H NMR (400 MHz, Chloroform-d) δ 7.06 (q, J = 8.16 Hz, 1H), 6.80-6.73(m, 1H), 6.66-6.61 (m, 2H), 5.88 (d, J = 18.04, 1H), 5.60 (d, J = 11.7,1H), 5.48 (s, 1H) ppm.

Step 2

Palladium on carbon (2.9 g, 10 %w/w, 2.3877 mmol) was added to a stirredsolution of 3-fluoro-2-vinyl-phenol (14.5 g, 94.470 mmol) in ethanol(145 mL). The mixture was degassed by bubbling through nitrogen gas for10 minutes. The reaction mixture was stirred under a balloon pressure ofhydrogen for 6h. The mixture was filtered through celite, washing withethanol, and the filtrate concentrated in vacuo. Purification by flashchromatography (SiO₂, 0-1 % EtOAc in hexanes) gave2-ethyl-3-fluoro-phenol (13 g, 93%) as a colourless oil. ¹H NMR (400MHz, Chloroform-d) δ 7.0 (q, J = 7.96 Hz, 1H), 6.62 (t, J = 8.7 Hz, 1H),6.54 (d, J = 8.08 Hz, 1H), 4.90 (br s, 1H), 2.66 (q, J = 7.24 Hz, 2H),1.17 (t, J = 7.52 Hz, 3H) ppm.

Step 3

NBS (14 g, 78.659 mmol) was added portion wise to a stirred solution of2-ethyl-3-fluoro-phenol (13 g, 88.117 mmol) and isopropylamine (4.6920g, 6.9 mL, 79.377 mmol) in DCM (274 mL) at -10° C. The reaction mixturewas stirred for 15 minutes. The reaction was quenched by addition of a2N aqueous solution of HCl. The mixture was extracted with DCM (2 × 500mL). The combined organic layers were dried (Na₂SO₄) and concentrated invacuo. Purification by flash chromatography (SiO₂, 0-1 % EtOAc inhexanes) gave 6-bromo-2-ethyl-3-fluoro-phenol (11 g, 55%) as acolourless oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.23 (dd, J = 4.76 Hz,J = 5.8 Hz, 1H), 6.55 (t, J = 8.72 Hz, 1H), 5.6 (d, J = 1.64 Hz, 1H),2.74 (q, J = 7.08 Hz, 2H), 1.16 (t, J = 7.4 Hz, 3H) ppm.

Step 4

Methyl iodide (13.680 g, 6 mL, 96.379 mmol) was added dropwise at 0° C.to a stirred solution of 6-bromo-2-ethyl-3-fluoro-phenol (11 g, 48.208mmol) and K₂CO₃ (16.5 g, 119.39 mmol) in DMF (110 mL). The reactionmixture was stirred for 12 h at ambient temperature. The mixture wasdiluted with ice water (250 mL). The aqueous phase was extracted withhexane (3 × 500 mL). The organic layer was separated, dried (MgSO₄),filtered and concentrated in vacuo. Purification by flash chromatography(SiO₂, 0-1 % EtOAc in hexanes) gave1-bromo-3-ethyl-4-fluoro-2-methoxy-benzene (11 g, 94%) as a colourlessoil. ¹H NMR (400 MHz, Chloroform-d) δ 7.32 (dd, J = 6.08 Hz, J = 6.04 Hz1H), 6.72 (t, J = 8.84 Hz, 1H), 3.84 (s, 3H), 2.70 (q, 2H), 1.18 (t, J =7.52 Hz, 3H) ppm.

Intermediate G 3-Bromo(Difluoromethyl)-2-Methoxypyridine

Step 1

Sodium methoxide (20 mL of 25 %w/v solution in MeOH, 92.552 mmol) wasadded at 0° C. to a stirred solution of3-bromo-2-chloro-6-methyl-pyridine (8 g, 38.747 mmol) in MeOH (50 mL) ina sealed tube. The reaction mixture was heated at 100° C. for 16 h. Thereaction mixture was concentrated in vacuo. The residue was diluted withwater (100 mL) and extracted with EtOAc (3 × 100 mL). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated in vacuoto give 3-bromo-2-methoxy-6-methyl-pyridine (5.5 g, 70%) as a colourlessoil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (d, J = 7.7 Hz, 1H), 6.76 (d, J =7.7 Hz, 1H), 3.88 (s, 3H), 2.35 (s, 3H) ppm. ESI-MS m/z calc. 200.9789,found 202.01 (M+1)⁺; Retention time: 1.69 minutes.

Step 2

KMnO₄ (13 g, 82.261 mmol) was added at ambient temperature to a stirredsolution of 3-bromo-2-methoxy-6-methyl-pyridine (5.5 g, 27.221 mmol) intert-butanol (150 mL) and water (300 mL). The reaction mixture washeated at 70° C. for 16 h. The reaction mixture was quenched by additionof a 1 M aqueous solution of HCl (80 mL). The resulting mixture wasstirred for 30 min, filtered and washed with EtOAc (2 × 100 mL). Themother liquors were extracted with EtOAc (2 × 50 mL). The combinedorganic layers were washed with a 0.5 N aqueous solution of NaOH (2 ×100 mL). The aqueous layer was collected, acidified by addition of a 12Naqueous solution of HCl and extracted with DCM (2 × 100 mL). Thecombined organic extracts were washed with brine, dried (Na₂SO₄),filtered and concentrated in vacuo to give5-bromo-6-methoxy-pyridine-2-carboxylic acid (3.1 g, 49%) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.27 (br s, 1H), 8.19 (d, J = 7.9Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 3.98 (s, 3H) ppm. ESI-MS m/z calc.230.9531, found 232.0 (M+1)⁺; Retention time: 1.34 minutes.

Step 3

Sodium carbonate (1.5 g, 14.153 mmol) was added to a stirred solution of5-bromo-6-methoxy-pyridine-2-carboxylic acid (3 g, 12.929 mmol) in DMF(40 mL). Methyl iodide (3.8760 g, 1.7 mL, 27.308 mmol) was then addedand the mixture was stirred at ambient temperature for 16 h. Thereaction mixture was quenched by addition of ice cold water (50 mL). Theaqueous phase was extracted with ethyl acetate (3 × 50 mL). The combinedorganic layers were washed with water (2 × 100 mL), brine (50 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to give methyl5-bromo-6-methoxy-pyridine-2-carboxylate (2.02 g, 63%) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (d, J = 7.8 Hz, 1H), 7.59 (d, J= 7.8 Hz, 1H), 3.98 (s, 3H), 3.87 (s, 3H) ppm. ESI-MS m/z calc.244.9688, found 246.1 (M+1)⁺; Retention time: 3.21 minutes.

Step 4

Diisobutylaluminum hydride (14 mL of 25 %w/v solution in toluene, 24.610mmol) was added at -78° C. to a stirred solution of methyl5-bromo-6-methoxy-pyridine-2-carboxylate (2 g, 8.128 mmol) in DCM (80mL). The reaction mixture was stirred at ambient temperature for 1 h.The reaction mixture was quenched by addition of a saturated aqueoussolution of sodium tartrate (50 mL). The mixture was stirred for 30 minthen extracted with DCM (3 × 100 mL). The combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo to give(5-bromo-6-methoxy-2-pyridyl)methanol (1.62 g, 91%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 7.99 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 7.6 Hz,1H), 5.45 (t, J = 11.8 Hz, 1H), 4.45 (d, J = 5.9 Hz, 2H), 3.89 (s, 3H)ppm. ESI-MS m/z calc. 216.9738, found 218.0 (M+1)⁺; Retention time: 2.93minutes.

Step 5

MnO₂ (8 g, 92.021 mmol) was added to a stirred solution of(5-bromo-6-methoxy-2-pyridyl)methanol (1.6 g, 7.3378 mmol) in DCM (80mL). The reaction mixture was stirred at ambient temperature for 16 h.The reaction mixture was filtered and concentrated in vacuo to give5-bromo-6-methoxy-pyridine-2-carbaldehyde (1.22 g, 77%) as off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 8.29 (d, J = 7.7 Hz,1H), 7.49 (d, J = 7.7 Hz, 1H), 4.03 (s, 3H) ppm.

Step 6

DAST (1.9740 g, 1.5 mL, 12.246 mmol) was slowly added at -20° C. to astirred solution of 5-bromo-6-methoxy-pyridine-2-carbaldehyde (1.2 g,5.5547 mmol) in DCM (30.000 mL). The reaction mixture was stirred atambient temperature for 16 h. The reaction mixture was quenched byaddition of ice-water. The pH of the solution was adjusted to 8-10 byaddition of solid sodium hydrogen carbonate. The organic phase wascollected, washed with water and brine, dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification by flash chromatography (SiO₂, 100%hexanes) gave 3-bromo-6-(difluoromethyl)-2-methoxy-pyridine (900 mg,65%) as pale yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (d, J = 7.8Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.03 - 6.75 (m, 1H), 3.96 (s, 3H)ppm.

Intermediate H Ethyl 4-Amino-5-Fluoropicolinate

Step 1

TEA (66.17 g) was added to a mixture of 2-bromo-5-fluoropyridin-4-amine(25 g, 0.131 mol) in DCM (250 mL) at 25-30° C. under a nitrogenatmosphere. The reaction mixture was cooled down to 15-20° C. Bocanhydride (57.13 g, 0.262 mol) was slowly added over 15 to 30 min. A 3to 5° exotherm was observed. The temperature was raised to 25-30° C. andmaintained for 24-36 h. Further TEA (13.23 g, 0.131 mol) and Bocanhydride (14.27 g, 0.065 mol) were added and the mixture was stirredfor a further 12-18 h at 25-30° C. The reaction mixture was quenched byslow addition of water (250 mL) at 10-20° C. over 1-2 h. The aqueouslayer was separated and extracted with DCM (125 mL x 2). The combinedorganic extracts were washed with a 10% aqueous solution of NaCl (250mL), dried ( Na₂SO₄), filtered and concentrated in vacuo. EtOAc (25 ml)was added to the brown colour solid and the mixture was stirred for10-15 min at 25-30° C. Hexane (50.0 mL) was slowly added at 25-30° C.,which caused a solid to precipitate. The mixture was stirred for 30 to45 min at 25-30° C. The solid was filtered, washed with hexane (12.5 mL)and dried under vacuum for 2-3 h at 40-45° C. to give tert-butyl(2-bromo-5-fluoropyridin-4-yl)carbamate (26.68 g, 70% yield). ¹H NMR(400 MHz, Chloroform-d) δ 8.33 (d, J = 6.0 Hz, 1H), 8.11 (d, J = 2.4 Hz,1H), 6.91 (br s, 1H), 1.56 (s, 9H) ppm.

Step 2

Pd(dppf)Cl₂ (7.54 g, 10.3 mmol) and TEA (15.64 g, 154.5 mmol) were addedto a mixture of tert-butyl (2-bromo-5-fluoropyridin-4-yl)carbamate (15g, 51.25 mmol) in ethanol (300 mL) at 25-30° C. under nitrogenatmosphere in a Parr bottle. The resulting mixture was shaken in theParr hydrogenator under a carbon monoxide pressure of 60 psi at 75-80°C. for 16-20 h. The reaction mixture was cooled down to 25-30° C. Themixture was filtered through a pad of celite and washed with ethanol(150 mL). The filtrates were concentrated concentrated in vacuo at40-45° C. Purification by flash chromatography (SiO₂, 0 to 10% EtOAc inhexanes) gave ethyl 4-((tert-butoxycarbonyl)amino)-5-fluoropicolinate(10 g, 68%). ¹H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 6.4 Hz, 1H),8.46 (d, J = 2.0 Hz, 1H), 6.95 (br s, 1H), 4.46 (q, J = 7.2 Hz, 2H),1.56 (s, 9H), 1.43 (t, J = 7.2 Hz, 3H) ppm.

Step 3

Ethyl 4-((tert-butoxycarbonyl)amino)-5-fluoropicolinate (14 g, 49.25mmol) was stirred at ambient temperature in a mixture of TFA (56 mL) andDCM (140 mL). Upon reaction completion, the mixture was concentrated invacuo and the pH of the solution was adjusted to 8-9 by addition of asaturated solution of sodium bicarbonate. The aqueous phase wasextracted with ethyl acetate. The organic extracts were concentrated invacuo to give ethyl 4-amino-5-fluoropicolinate (7.53 g, 83%). ¹H NMR(400 MHz, DMSO-d₆) δ 8.17 (d, J = 3.2 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H),6.50 (br s, 1H), 4.26 (q, J = 6.8 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H) ppm.ESI-MS m/z calc. 184.0648, found 184.84 (M+1)⁺.

Intermediate I Methyl 4-Chloro-6-Fluoropicolinate

Step 1

To a stirred mixture of methyl 4-chloropyridine-2-carboxylate (625 mg,3.643 mmol) in acetonitrile (15 mL) was added silver fluoride (1.7 g,11.655 mmol) in one portion at room temperature. The reaction mixturewas stirred at room temperature for 18 h. Additional silver fluoride(530 mg, 3.634 mmol) was added and the stirring was continued for anadditional 24 h. The reaction mixture was poured into a saturatedaqueous solution of sodium bicarbonate (50 mL) and ethyl acetate (50 mL)and filtered through a pad of Celite. The organic extracts were washedwith brine (20 mL), dried (Na₂SO₄) and concentrated in vacuo.Purification by flash chromatography (25 g SiO₂, 0 to 100% EtOAc inheptane) gave methyl 4-chloro-6-fluoropicolinate (200 mg, 28%) as awhite solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.03 (dd, J = 1.4, 0.9 Hz,1H), 7.18 (dd, J = 2.7, 1.8 Hz, 1H), 4.00 (s, 3H) ppm.

Intermediate J Methyl 4-Aminopicolinate-5-d

Step 1

A mixture of methyl 4-amino-5-iodo-pyridine-2-carboxylate ( 1 g, 3.5965mmol), K₂CO₃ (0.5 g, 3.6178 mmol) and palladium on carbon (200 mg, 5%w/w, 0.0940 mmol) in methanol-d4 (8 mL) was stirred at room temperatureunder an atmosphere of deuterium gas (balloon) for 20 h. The mixture wasfiltered through Celite, washing with methanol and concentrated in vacuoto give a white solid. Purification by reverse phase chromatography(Biotage Isolera, 30 g, SiliaSep C18 Monomeric 25 µm Silicycle flashcartridge, 0 to 100% acetonitrile containing 0.1% ammonium hydroxide inwater containing 0.1% ammonium hydroxide) to give methyl4-amino-5-deuterio-pyridine-2-carboxylate (77 mg, 13%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (s, 1H), 7.18 (s, 1H), 6.29 (br s, 2H),3.77 (s, 3H) ppm. ESI-MS m/z calc. 153.0649, found 154.08 (M+1)⁺.

Intermediate K Methyl 4-Chloropicolinate-3-d

Step 1

A solution of 2,2,6,6-tetramethylpiperidine (3.442 g, 4.147 mL, 24.369mmol) in THF (40 mL) was cooled to -50° C. ^(n)BuLi (1.6 M in hexanes)(20.307 mL of 1.6 M, 32.492 mmol) was added dropwise over 10 min. Thereaction mixture was stirred for 5 min, then pyridine-2-carboxylic acid(1 g, 8.1229 mmol) was added. After stirring for 10 min, the reactionmixture was allowed to warm to 0° C. and deuterium oxide (813.40 mg,0.813 mL, 40.614 mmol) was added. The reaction mixture was stirred for30 min. The mixture was concentrated in vacuo to give a pale brown solidwhich was stirred in a 9:1 mixture of DCM and MeOH (20 mL) for 30 min.The solid was filtered and the filtrates concentrated in vacuo to give afirst crop of 3-deuteriopyridine-2-carboxylic acid (353 mg, 32%) . Thesolid was subjected a second time to the same treatment to give a secondcrop of 3-deuteriopyridine-2-carboxylic acid (214 mg, 19%). ¹H NMR (400MHz, Methanol-d4) δ 8.53 (q, J = 2.1 Hz, 1H), 7.87 (dd, J = 7.3, 1.4 Hz,1H), 7.43 (dd, J = 7.6, 4.8 Hz, 1H) ppm. 93% deuterium incorporationobserved by NMR.

Step 2

DMF (47.200 mg, 0.05 mL, 0.6457 mmol) was added at 45° C. to a solutionof thionyl chloride (1.957 g, 1.2 mL, 16.451 mmol).3-deuteriopyridine-2-carboxylic acid (400 mg, 3.0617 mmol) was added andthe reaction mixture was heated at 75° C. for 16 h. The reaction mixturewas cooled to room temperature and toluene was added (1 mL). The mixturewas concentrated in vacuo and the same process was repeated. Methanolwas added and the mixture was stirred at room temperature for 30 minutesthen concentrated in vacuo. The residue was partitioned between asaturated aqueous solution of sodium hydrogen carbonate (3 mL) and ethylacetate. The aqueous phase was extracted with ethyl acetate and thecombined organic extracts were dried (MgSO4), filtered and concentratedin vacuo. Purification by flash chromatography (Biotage Isolera, 25 g,SiliaSep 25 µm Silicycle flash cartridge, 30% to 100% ethyl acetate inheptane) gave methyl 4-chloro-3-deuterio-pyridine-2-carboxylate (210 mg,38%) as a pale brown solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.64 (d, J= 5.0 Hz, 1H), 7.49 (d, J = 5.0 Hz, 1H), 4.02 (s, 3H) ppm.

Intermediate L Methyl 4-Chloropicolinate-6-d

Step 1

A mixture of 2-carboxypyridine 1-oxide (2.94 g, 21.135 mmol) and sodiumdeuteroxide (5 mL of 40 %w/v solution in water, 46.493 mmol) indeuterated water (5 mL) was stirred at 80° C. for 4 h. The reactionmixture was cooled to ambient temperature. The mixture was poured intoconcentrated hydrochloric acid (6 mL) at 0° C. and the solid collectedby filtration. The filtrate was acidified to pH 1 with concentratedhydrochloric acid and additional solid collected by filtration. Thesolids were combined to give 2-carboxypyridine 1-oxide-6-d (2.08 g, 67%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 18.67 (s, 1H), 8.28 (dd, J= 7.6, 2.3 Hz, 1H), 7.91-7.85 (m, 2H) ppm. 95% deuterium incorporationobserved by NMR.

Step 2

POCl₃ (822.50 mg, 0.5 mL, 5.3642 mmol) was added to a stirred mixture oftoluene (2.5 mL) and DMF (5 mL) at room temperature. The mixture wascooled to 0° C. and 2-carboxypyridine 1-oxide-6-d (150 mg, 1.0170 mmol)was added. The reaction mixture was stirred for 5 min at 0° C. then, fora further 18 h at ambient temperature. The mixture was concentrated invacuo to approximately 50% of its volume. Methanol (5 mL) was added, andthe mixture was again concentrated in vacuo to approximately 50% of itsvolume. The obtained solution was added to an aqueous saturated solutionof NaHCO₃ (20 mL) and extracted with ethyl acetate (3 × 10 mL). Theorganic extracts were washed with brine (10 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The crude material was combined withanother batch of the same scale. Purification by flash chromatography(Biotage Isolera, 12 g, SiliaSep 25 µm Silicycle flash cartridge, 0 to50% ethyl acetate in heptane) gave methyl 4-chloropicolinate-6-d (29 mg,14%) as a colourless oil. ¹H NMR (400 MHz, Chloroform-d) δ 8.14 (d, J =1.5 Hz, 1H), 7.49 (s, 1H), 4.01 (s, 3H) ppm. ESI-MS m/z calc. 172.015,found 173.01 (M+1)⁺; Retention time: 1.15 minutes.

Example 34 E-VIPR Assay Detecting and Measuring Na_(v) InhibitionProperties

Sodium ion channels are voltage-dependent proteins that can be activatedby inducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use, referred to asE-VIPR, are described in International Publication No. WO 2002/008748 A3and C.-J. Huang et al. Characterization of voltage-gated sodium channelblockers by electrical stimulation and fluorescence detection ofmembrane potential, 24 Nature Biotech. 439-46 (2006), both of which areincorporated by reference in their entirety. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, andparallel electrode pairs that are inserted into assay plate wells. Underintegrated computer control, this instrument passes user-programmedelectrical stimulus protocols to cells within the wells of themicrotiter plate.

16-20 hours prior to running the assay on E-VIPR, HEK cells expressing atruncated form of human Na_(v) 1.8 with full channel activity wereseeded into microtiter 384-well plates, pre-coated with matrigel, at adensity of 25,000 cells per well. 2.5-5% KIR2.1 Bacmam virus was addedto the final cell suspension before seeding into cell plates. HEK cellswere grown in Dulbecco’s Modified Eagle’s Medium (DMEM) supplementedwith 10% FBS (Fetal Bovine Serum, qualified; Sigma #F4135), 1% NEAA(Non-Essential Amino Acids, Gibco #11140), 1% HEPES (Gibco #15630), 1%Pen-Strep (Penicillin-Streptomycin; Gibco #15140) and 5 µg/mlBlasticidin (Gibco #R210-01). Cells were expanded in vented cap cellculture flasks, with 90-95% humidity and 5% CO₂.

Reagents and Stock Solutions:

-   100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO-   Compound Plates: Coming 384-well Polypropylene Round Bottom #3656-   Cell Plates: 384-well tissue culture treated plates (Greiner    #781091-1B)

2.5-5% KIR 2.1 Bacmam virus (produced in-house), prepared as describedin Section 3.3 of J. A. Fornwald et al., Gene Expression in MammalianCells Using BacMam, a Modified Baculovirus System, 1350 Methods inMolecular Biology 95-116 (2016), the entire contents of which areincorporated by reference. The concentration used can be dependent onviral titer of each batch.

5 mM DiSBAC₆(3), a voltage sensitive oxonol acceptor (CAS number169211-44-3;5-[3-(1,3-dihexylhexahydro-4,6-dioxo-2-thioxo-5-pyrimidinyl)-2-propen-1-ylidene]-1,3-dihexyldihydro-2-thioxo-4,6(1H,5H)-pyrimidinedione),in dry DMSO. The preparation of DiSBAC₆(3) is analogous to that ofDiSBAC₄(3) as described in Voltage Sensing by Fluorescence ResonanceEnergy Transfer in Single Cells, Gonzalez, J.E. and Tsien, R.Y. (1995)Biophys. J. 69, 1272-1280.

5 mM CC2-DMPE, a commercially available membrane-bound coumarinphospholipid FRET donor (ThermoFisher Scientific catalog number K1017,CAS number 393782-57-5; tetradecanoic acid,1,1′-[(1R)-1-[8-(6-chloro-7-hydroxy-2-oxo-2H-1-benzopyran-3-yl)-3-hydroxy-3-oxido-8-oxo-2,4-dioxa-7-aza-3-phosphaoct-1-yl]-1,2-ethanediyl]ester) was prepared in dry DMSO. See also, Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer,Gonzalez, J.E. and Tsien, R.Y. (1997) Chem. Biol. 4, 269-277.

Voltage Assay Background Suppression Compound (VABSC-1) is prepared inH₂O (89-363 mM, range used to maintain solubility)

Human Serum (HS, Millipore #S1P1-01KL, or Sigma SLBR5469V and SLBR5470Vas a 50%/50% mixture, for 25% assay final concentration)

Bath1 Buffer:

Sodium Chloride 160 mM (9.35 g/L), Potassium Chloride, 4.5 mM (0.335g/L), Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous) 1 mM(0.095 g/L), Calcium Chloride 2 mM (0.222 g/L), HEPES 10 mM (2.38 g/L)in water.

Na/TMA Cl Bath1 Buffer:

Sodium Chloride 96 mM (5.61 g/L), Potassium Chloride 4.5 mM (0.335 g/L),Tetramethylammonium (TMA)-Cl 64 mM (7.01 g/ L), Glucose 10 mM (1.8 g/L),Magnesium Chloride (Anhydrous) 1 mM (0.095 g/L), Calcium Chloride 2 mM(0.222 g/L) HEPES 10 mM (2.38 g/L) in water.

Hexyl Dye Solution (2X concentration):

Bath1 Buffer containing 0.5% β-cyclodextrin (made fresh prior to eachuse, Sigma #C4767), 8 µM CC2-DMPE and 2 µM DiSBAC₆(3). The solution wasmade by adding 10% Pluronic F127 stock equal to combined volumes ofCC2-DMPE and DiSBAC₆(3). The order of preparation was first mix Pluronicand CC2-DMPE, then add DiSBAC₆(3), then while vortexing addBath1/β-Cyclodextrin.

Compound Loading Buffer (2X concentration): Na/TMA Cl Bath1 Buffercontaining HS (omitted in experiments run in the absence of human serum(HS))50%, VABSC-1 1 mM, BSA 0.2 mg/ml (in Bath-1), KCl 9 mM, DMSO 0.75%.

Assay Protocol (7 key Steps):

1) To reach the final concentration in each well, 400 nL of eachcompound was pre-spotted (in neat DMSO) into polypropylene compoundplates at 250× desired final concentration from an intermediate stockconcentration of 0.075 mM, in an 11 point dose response, 3-folddilution, resulting in a top dose of 300 nM final concentration in thecell plate. Vehicle control (neat DMSO), and positive control (anestablished Na_(v) 1.8 inhibitor, 25 µM final in assay in DMSO) wereadded manually to the outermost columns of each plate respectively. Thecompound plate was backfilled with 45 µL per well of Compound LoadingBuffer resulting in a 250 fold dilution of compound following a 1:1transfer of compound into the cell plate (see Step 6). Final DMSOconcentration for all wells in the assay was 0.625% (0.75% DMSO wassupplemented to the Compound Loading Buffer for a final DMSOconcentration of 0.625%). This assay dilution protocol was adjusted toenable a higher dose range to be tested in the presence of HS or if thefinal assay volume was altered.

2) Hexyl Dye Solution was prepared.

3) Cell plates were prepared. On the day of the assay, the media wasaspirated, and the cells were washed three times with 80 µL of Bath-1buffer, maintaining 25 µL residual volume in each well.

4) 25 µL per well of Hexyl Dye Solution was dispensed into the cellplates. The cells were incubated for 20 minutes at room temperature orambient conditions in darkness.

5) 45 µL per well of Compound Loading Buffer was dispensed into compoundplates.

6) The cell plates were washed three times with 80 µL per well of Bath-1Buffer, leaving 25 µL of residual volume. Then 25 µL per well fromcompound plate was transferred to each cell plate. The mixture wasincubated for 30 minutes at room temperature/ambient conditions.

7) The cell plate containing compound was read on E-VIPR using thecurrent-controlled amplifier to deliver stimulation wave pulses using asymmetrical biphasic waveform. The user-programmed electrical stimulusprotocols were 1.25-4 Amps and 4-6 millisecond pulse width (dependent onelectrode composition) were delivered at 10 Hz for 10 seconds. Apre-stimulus recording was performed for each well for 0.5 seconds toobtain the un-stimulated intensities baseline. The stimulatory waveformwas followed by 0.5 seconds of post-stimulation recording to examine therelaxation to the resting state. All E-VIPR responses were measured at200 Hz acquisition rate.

Data Analysis

Data were analyzed and reported as normalized ratios of emissionintensities measured in the 460 nm and 580 nm channels. The response asa function of time was reported as the ratios obtained using thefollowing formula:

$\text{R}\left( \text{t} \right)\text{=}\frac{\left( \text{intensity}_{\text{460 nm}} \right)}{\left( \text{intensity}_{\text{580 nm}} \right)}$

The data were further reduced by calculating the initial (R_(i)) andfinal (R_(f)) ratios. These were the average ratio values during part orall of the pre-stimulation period and during sample points during thestimulation period. The fluorescence ratio (R_(f)/R_(i)) was thencalculated and reported as a function of time.

Control responses were obtained by performing assays in the presence ofthe positive control, and in the absence of pharmacological agents (DMSOvehicle negative control). Responses to the negative (N) and positive(P) controls were calculated as above. The compound antagonist %activity A was then defined as:

$\text{A} = \frac{\text{X - N}}{\text{P - N}} \times 100$

where X is the ratio response of the test compound. Using this analysisprotocol, dose response curves were plotted and IC₅₀ values weregenerated for various compounds of the present invention as reportedbelow in Tables 1 and 2.

TABLE 1 IC₅₀ Values of Compounds of the Invention Generated in thePresence of Human Serum in the E-VIPR Assay (A = IC₅₀ < 0.01 µM; B 0.1µM > IC₅₀ ≥ 0.01 µM; C = 1 µM > IC₅₀ ≥ 0.1 µM; D = IC₅₀ ≥ 1 µM) Cmpd #IC₅₀ (µM) 1 B 2 C 3a D 3b A 4 D 5 B 6 D 7 A 8 D 9 A 10 D 11 A 12 D 13 B14 D 15 A 16 D 17 A 18 A 19 A 20 D 21 D 22 B 23 B 24 D 25 A 26 A 27 B 28B 29 D 30 C 31 D 32 A 33 C 34 D 35 C 36 D 37 C 38 D 39 C 40 D 41 B 44 A45 B 46 D 47 B 51 D 52 A 53 A 54 C 55 A 56 A 57 D 58 D 59 D 60 B 61 C 63D 64 B 65 D 66 C 67 D 68 B 69 D 70 D 71 D 72 B 73 D 74 B 75 D 76 C 77 D78 B 79 D 80 D 81 C 82 D 83 C 84 D 85 D 86 D 87 C 88 D 89 A 90 D 91 C 92D 93 A 94 A 95 D 96 D 97 D 98 D 99 D 100 D 101 D 102 D 103 D 104 D 105 B106 D 107 D 108 C 109 D 110 C 111 D 112 C 113 B 115 A 116 A 137 D 138 B146 B 150 D 151 B

TABLE 2 IC₅₀ Values of Compounds of the Invention Generated in theAbsence of Human Serum in the E-VIPR Assay (A = IC₅₀ < 0.01 µM; B = 0.1µM > IC₅₀ ≥ 0.01 µM; C = 1 µM > IC₅₀ ≥ 0.1 µM; D = IC₅₀ ≥ 1 µM) Cmpd #IC₅₀ (µM) 42 A 43 C 50 B 114 B 117 B 118 A 119 A 120 B 121 A 122 A 123 A124 A 126 A 127 A 128 A 128 B 129 A 131 D 132 A 133 B 134 C 135 D 136 A139 D 140 B 141 D 147 A 148 A 149 A 152 A

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

What is claimed is:
 1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein: X^(2a) isC-R^(2a); X^(4a) is C-R^(4a); X^(5a) is C-R^(5a); X^(6a) is C-R^(6a);each R is independently H or C₁-C₆ alkyl; R^(2a), R^(4a), R^(5a), andR^(6a) are each independently H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;R^(4b1) and R4^(b2) are each independently H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, or C₁-C₆ haloalkyl; R^(5b1) and R^(5b2) are eachindependently H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or C₁-C₆ haloalkyl;X^(3c) is N or C-R^(3c); X⁴° is N or C-R^(4c); X^(5C) is N or C-R^(5c)X^(6c) is N or C-R^(6c); R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, or-L¹-L²-(C₃-C₆ cycloalkyl), wherein said cycloalkyl or R^(2c) isoptionally substituted with 1-2 halo; L¹ is a bond or O; L² is a bond orC₁-C₆ alkylene; R^(3c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;R^(4c) is H, halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(5c) is H, halo,C₁-C₆ alkyl, or C₁-C₆ haloalkyl; and R^(6c) is H, halo, C₁-C₆ alkyl, orC₁-C₆ haloalkyl; and provided that no more than one of X^(3c), X^(4c),X^(5c), and X^(6c) are N.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R^(4b1) and R4^(b2)are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R^(5b1) andR^(5b2) are each independently H, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;X^(3c) is C-R^(3c), X^(4c) is C-R^(4c); X^(5c) is C-R^(5c); X^(6c) isC-R^(6c); and R^(2c) is H, OH, halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, or C₁-C₆ haloalkoxy.
 3. The compound of claim 1, wherein thecompound has formula (I-A)

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, wherein the compound has formula (I-B)

or a pharmaceutically acceptable salt thereof. 5-37. (canceled)
 38. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein the compound is selected from

.
 39. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is selected from

(2R,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluromethoxy)-4-fluoro-phenyil-4.5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy-4-fluorophenyl]4.5-dimethyl-5-(trifluosomethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethoxy)-4-fluoro-phenyl]-4.5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluotomethoxy)-4-fluoro-phenyl]-4.5-dimethyl-5-(drifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4S,5S)-N-(3-carbamoryl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4.5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluor-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]4,5-dimethyl-5-trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-difluoromethoxy)-4-fluoro-phenyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-[2-(difluoromethoxy)-4-fluoro-phenyl]-4,5-dimethyl-5-(trifluoromethy)tetrahydrofuran-2-carboxamide,(2R,3R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(-3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,5S)-N-3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3.4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4S,5R)-N-(3-carbamoylphenyl)-3-[2-difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4R,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4S,5S)-N-(3-carbamoylphonyl)-3-[2-(difluomethoxy)-3,4-difluoro-phenyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4.5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4R,5S)-N-(3-carbamoylphenyl)-3-[2-difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4S,5R)-N-(3-carbamoylphenyl)-3-[2-difluoromethoxy)-3,4-difluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4S,5R)-N-(3-carbamoylphenyl)-3-[2difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4R,5R)-N-(3-carbamoylphenyl)-3-(difluoromethoxy)-3,4-difluoro-phenyl-4,5-dimethyl-5-(trfluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4R,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbixamide,(2S,3S,4S,5R)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4S,5S)-N-(3-carbamoylphenyl)-3-[2-(difluoromethoxy)-3,4-difluoro-phenyl]4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4R,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(triflouromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4S,5R)-N-(3carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4R,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2R,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3R,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4R,5S)-N(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,(2S,3S,4S,5R)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide,and(2S,3S,4S,5S)-N-(3-carbamoyl-4-fluoro-phenyl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide.40-96. (canceled)
 97. A pharmaceutical composition comprising thecompound of claim 1, or a pharmaceutically acceptable salt thereof, andone or more pharmaceutically acceptable carriers or vehicles.
 98. Amethod of inhibiting a voltage-gated sodium channel in a subjectcomprising administering to the subject the compound of claim 1, or apharmaceutically acceptable salt thereof.
 99. The method of claim 98,wherein the voltage-gated sodium channel is Navl.8.
 100. A method oftreating or lessening the severity in a subject of chronic pain, gutpain, neuropathic pain, musculoskeletal pain, acute pain, inflammatorypain, cancer pain, idiopathic pain, postsurgical pain, visceral pain,multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence,pathological cough, or cardiac arrhythmia comprising administering tothe subject an effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof.
 101. The method of claim 100,where the method comprises treating or lessening the severity in thesubject of neuropathic pain.
 102. The method of claim 101, wherein theneuropathic pain comprises post-herpetic neuralgia, small fiberneuropathy, idiopathic small-fiber neuropathy, or diabetic neuropathy.103-104. (canceled)
 105. The method of claim 100, wherein the methodcomprises treating or lessening the severity in the subject ofmusculoskeletal pain.
 106. The method of claim 105, wherein themusculoskeletal pain comprises osteoarthritis pain.
 107. The method ofclaim 100, wherein the method comprises treating or lessening theseverity in the subject of acute pain.
 108. The method of claim 107,wherein the acute pain comprises acute postoperative pain.
 109. Themethod of claim 100, wherein the method comprises treating or lesseningthe severity in the subject of postsurgical pain.
 110. The method ofclaim 109, wherein the postsurgical pain comprises bunionectomy pain,hemiorrbaphy pain, or abdominoplasty pain. 111-112. (canceled)
 113. Themethod of claim 100, wherein the method comprises treating or lesseningthe severity in the subject of visceral pain.
 114. A method of treatingor lessening the severity in a subject of pain comprising administeringto the subject an effective amount of the compound of claim 1, or apharmaceutically acceptable salt thereof .
 115. The method of claim 100,wherein said subject is treated with one or more additional therapeuticagents administered concurrently with, prior to, or subsequent totreatment with the compound.
 116. (canceled)